Ongoing projects

Design, synthesis and biological evaluation of novel ferroptosis and necroptosis inhibitors. 01/10/2021 - 30/09/2022

Abstract

Different types of cells deaths play a key role in the pathogenesis of many different diseases such as neurodegenerative disorders, multiorgan injury and cancer. In addition to the well-known apoptosis, novel forms of regulated necrosis have been discovered. Particularly, ferroptosis and necroptosis have emerged as new types of non-apoptotic form of cell death of which ferroptosis is involved in reactive oxygen species (ROS) formation. ROS accumulation promotes damage in different organs and tissues, and could potentially start the release of pro-inflammatory cytokines leading to inflammation and cell membrane disruption. The aim of the project is twofold: 1) the design and synthesis of novel radical trapping agents (RTAs) to hinder the accumulation of lipid hydroperoxides linked with ferroptosis and 2) the design and synthesis of novel receptor interacting serine/threonine kinase 1 (RIPK1) inhibitors to prevent necroptosis. Ferroptosis project: recently, in the MedChem group at the university of Antwerp (UAMC), two novel compounds, namely UAMC-0003203 and UAMC-0003206 have been published and patented as new RTAs able to block the lipid hydroperoxide formation. With higher potency, stability and solubility compared to the well-known benchmark compound Ferrostatin 1, the novel lead compounds can have a therapeutic potential in relevant ferroptosis-driven disease models. A novel library of ferroptosis inhibitors has been successfully synthetized aiming to improve potency, selectivity and ADME properties of the reference compounds. A new ferroptosis in vitro model will be developed in collaboration with prof. Dr. Tom Vanden Berghe to test the library of ferroptosis inhibitors. Necroptosis project: in the necroptosis pathway RIPK1 plays a pivotal role. RIPK1 is a key mediator of inflammation, which is considered the core-mechanism of many pathologies. Thus, RIPK1 is considered a an emerging kinase target in the field of regulated necrosis. A library of Tozasertib analogues, able to selectively inhibit RIPK1, has been synthetized by UAMC. UAMC-0003063 and UAMC-0003064 are the most potent compounds of the library and the improvement of their potency, selectivity and ADME profile was the initial idea of the project. Recently, it was discovered that the GlaxoSmithKline compound GSK2656157, known as a Protein kinase R (PKR)-like ER kinase (PERK) inhibitor, was a potent and selective inhibitor for RIPK1. We therefor studied the differences between the two kinase enzymes PERK and RIPK1 and how the molecule interacts with the active binding site. The development of selective inhibitors is a challenge in the family of protein kinases due to their strong similarities in the ATP binding pocket. Particular attention is therefore given to the interaction with the allosteric pocket, also known as selectivity pocket. Based on a published RIPK1 crystal structure it was possible to further investigate the structural differences between PERK and RIPK1. The synthesis of a novel library of more selective RIPK1 analogues is now being finalized. In vitro tests will be performed to assess the potency and the binding affinity of the novel analogues.

Researcher(s)

Research team(s)

Design, Synthesis and Biochemical evaluation of novel serine protease activity-based probes. 01/10/2021 - 30/09/2022

Abstract

Serine proteases are a subgroup of the protease family involved in several physiological processes, including immune response, cell death and tissue healing. The upregulation of these proteases can increase inflammatory cytokines, degradation of extracellular matrix components, activation of PAR2 or MMP-9. We previously obtained an in vivo proof of concept with a multi-target serine protease inhibitor (UAMC-00050) in Dry Eye Disease (DED). Topical application of this compound in the eye of a tear-deficient dry eye rat animal model reduced both tissue damage and inflammatory parameters. Moreover, UAMC-00050 also cause a decrease in visceral hypersensitivity in a rat model of post-inflammatory visceral hypersensitivity. Therefore, we hypothesized that serine proteases play an essential role in both DED and Irritable Bowel Syndrome (IBS). The focus of this project is to characterize the proteases involved in DED and IBS. We are using activity-based protein profiling (ABPP), a proteomic technique where chemical probes are used for target identification and drug discovery research. Activity-based probes (ABPs) are small molecules that react covalently with the enzyme active site and facilitate the labelling of target proteins. Up-to-date, a series of 17 new ABPs, analogues from our inhibitor, were synthesized. The challenging synthesis of ABPs required extensive optimization of the synthetic pathways. The phosphonate warhead is crucial to target and bind irreversibly to trypsin-like serine proteases. All ABPs have been biochemically characterized by determining their IC50 in a panel of different serine proteases involved in immune responses. Several potent ABPs have been synthesised and characterized so far. Since ABPs need to bind covalently to the target protein efforts will now be made to describe the most potent probes' kinetic profile by progress curve assays. In addition jump dilution experiments will be performed to discriminate between inhibition mechanisms. In a last stage, ABPs that are potent against the serine proteases of interest and that undergo an irreversible inhibition mechanism will be used to label and identify upregulated proteases in biological samples of DED and IBS patients. Mass spectrometry and gel electrophoresis will be used to detect the ABPs. Identifying the upregulated proteases will allow the design and synthesis of more selective and potent compounds to treat DED and IBS.

Researcher(s)

Research team(s)

Validation of autophagy induction as a therapeutic strategy: from drug discovery and preclinical evaluation to safety investigation and biomarker research. 01/01/2021 - 31/12/2024

Abstract

Autophagy is a ubiquitous process that removes unnecessary or dysfunctional cellular components from the cytoplasm. Defective autophagy is currently emerging as a hallmark of many diseases. In this framework, there is strong interest in pharmacological agents that stimulate autophagy (so-called 'autophagy inducers'), as a potential treatment for these diseases. The unequivocal validation of autophagy induction as a therapeutic strategy, however, is far from established. Many obstacles persist, including the lack of druglike, selective autophagy inducers and readily translatable preclinical results that are obtained with such compounds. In addition, the availability of reliable biomarkers for autophagy and additional fundamental safety data for the approach, would strongly contribute to its validation. This proposal addresses existing limitations in the state-of-the art in the domain. We have recently carried out a phenotypic High-Throughput Screen (HTS) on a curated compound library. Members in this library were preselected from different providers based on in silico druglikeness scores. One compound family that was identified in the screen and maximally validated prior to this application, will be further optimized chemically for autophagy induction potency and biopharmaceutical properties. The biopharmaceutical profile of the best new representative will be thoroughly characterized in vivo, both involving PET-based pharmacokinetics and phenotypic pharmacodynamics. The compound will subsequently be investigated in two mouse models of diseases characterized by defective autophagy: atherosclerosis and Charcot-Marie-Tooth periferal neuropathy. In addition, we propose to investigate whether autophagy induction is intrinsically sufficiently safe as a therapeutic strategy. Existing hypotheses that autophagy induction could accelerate tumorigenesis and/or tumor growth will be investigated in vivo. In the same framework, metabolomics will be relied on to monitor eventual cellular stress fingerprints that result from chronic or long-term autophagy stimulation. Finally, metabolomics will also be relied on to identify cellular biomarkers of autophagy induction. The latter will be validated in plasma samples of animals that were systemically treated with autophagy inducers. Combined, we expect the knowledge and tools that are generated by this proposal to have strong impact on the field of autophagy research and ongoing endeavors to validate autophagy induction as a therapeutic strategy.

Researcher(s)

Research team(s)

Exploring a novel class of autophagy-inducing small molecules: chemical/biological investigation, target identification and validation in a mouse model of atherosclerosis. 01/11/2020 - 31/10/2023

Abstract

Autophagy is a normal physiological process that removes unnecessary or dysfunctional cellular components from the cytoplasm. Defective autophagy is currently emerging as a hallmark feature of many diseases. In this framework, basic research and drug development have a strong need for reliable, druglike autophagy inducers. In response, we recently carried out a phenotypic highthroughput screen on ~11.000 compounds that were preselected based on druglikeness parameters. In total, 36 potent autophagy inducers were identified. They belong to 10 distinct chemical families that previously have not been associated with autophagy induction. After thorough validation, potency and gross mode-of-action studies, 2 chemical families have been prioritized for further investigation. The proposal comprises the thorough investigation of the most promising family. Structure-Activity Relationships will be constructed and the pharmacophore identified. In addition, chemical optimization will be pursued to obtain analogues with further improved potency and a maximally favorable physico-chemical profile. All novel compounds will be thoroughly investigated in cells and the best performing molecule will be evaluated in an in vivo model of atherosclerosis. Finally, biochemical target identification will be approached via an ensemble of affinity-chromatography, phosphoproteomics and a kinase activity assay.

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Research team(s)

Evaluation of the applicability of well-tempered metadynamics simulations as a tool for computational design of inhibitors of dipeptidyl peptidase 8 and 9. 01/11/2020 - 31/10/2022

Abstract

Evaluation of the binding affinity of small molecules against therapeutically relevant proteins is currently performed using in vitro assays tailored to the specific problem at hand. However, despite their proven usefulness, compound solubility issues and limited chemical diversity imposed by the input compound library, emphasise some drawbacks. Fragment-based methods have also been introduced in which fragments are linked up with other fragments to grow into drug-like molecules. However, because such fragments are small, binding is weak and not always straightforward to detect. Hence, as an alternative to the experimental fragment-based screening, this project is investigating whether it is possible to use computational fragment-based drug design to identify fragments that might serve as starting points for further optimisation. The proposed method utilises metadynamics of the protein in combination with a number of small fragments in an explicit water box. The validity of the method will be tested on three 'real-world' protein targets, including dipeptidylpeptidase 4 (DPP4), DPP8 and DPP9. The crystal structures of these three dimeric enzymes have been determined, and at UAMC we have synthesized a large number of inhibitors and have biochemically characterized their corresponding cross-reactivities (selectivities), hence allowing us to evaluate whether computational fragment-based design can be modified to address selectivity issues within the drug design cycle.

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Research team(s)

Synthesis of a small library of a SurA hit compound, 20-40 analogues, 10 mg of each compound, at least 95% purity. 01/07/2020 - 31/12/2021

Abstract

SurA is a chaperone located in the periplasm of Gram-negative bacteria that is responsible for protecting outer membrane proteins from aggregation in the periplasm and facilitating their delivery to the beta-barrel assembly machinery for folding and insertion into the outer membrane. Inhibition of SurA leads to increased sensitivity to antibiotics and reduced pathogenicity. Therefore, SurA inhibitors have the potential to treat infections with gram-negative bacteria.

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Research team(s)

iMI-project - support - RespiriTB and RaspiriNTM 01/01/2020 - 31/12/2023

Abstract

Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. Finally, we will also target host-factors that are essential for the intracellular survival of NTM. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

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Project website

Development of new TCO-probes and their evaluation for a novel pre-targeted intracellular PET imaging strategy. 01/11/2019 - 31/10/2023

Abstract

Positron emission tomography (PET) imaging of radiolabeled monoclonal antibodies (mAb) is a powerful in vivo research tool with applications in diagnostic as well as in prognostic and therapeutic settings. The molecular precision of antigen-mAb interaction turns radiolabeled mAbs into highly specific radiotracers with a very high affinity. However, the high molecular weight and the long circulation times of mAbs are associated with unsatisfactory target to background ratios, thus requiring the use of long-lived isotopes which yields high radiation burden to the patient. A pretargeting strategy based in biorthogonal chemistry offers a solution to this problem. In this approach, the mAb with biorthogonal tag will be labeled in vivo with a short lived radiotracer through bioorthogonal reaction at the target site. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs internalize upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims to develop a novel pretargeted intracellular PET imaging strategy. We will develop novel cell permeable fluorinated trans-cyclooctene analogues (TCOs) and investigate their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

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Research team(s)

Impact of extracellular matrix organization in the tumor environment on efficacy of immunotherapy in DNA mismatch repair deficient tumors. 01/09/2019 - 31/08/2023

Abstract

Immunotherapy is revolutionizing the clinical management of multiple cancer types including DNA mismatch repair-deficient tumors (Galluzi et al., 2018). However, even in this preselected group of patients, good and complete response are achieved in only one fifth of the patients (Le et al., 2016; Le et al., 2017). Thus, there are still enormous opportunities for improvement. The presence of an immunosuppressive tumor environment may be key to further optimization of immunotherapy (Jiang et al., 2016). Extracellular matrix accumulation and rigidity, and neo-expression of matrix proteins may be involved in T cell exclusion from the proximity of cancer cells or impaired T cell functionality. Cancer-associated fibroblasts (CAF) create an imbalanced biomechanical force in the tumor by the deposition of extracellular matrix, and by their contractility and proteolytic activity. CAF are abundant in mismatch repair-deficient tumors and their presence is associated with poor disease outcome (Kalluri 2016). Clinical targeting of CAF has been challenging due to its heterogeneous nature. We propose to target CAF making use of commonly expressed fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) or protease activity by fibroblast-activation protein (FAP). The advantage of FGFR/PDGFR inhibitors and FAP inhibitors is their complementary targeting of CAF biology either growth/differentiation vs proteolysis. Thus, we will evaluate whether impeding immune cell infiltration/functionality by CAF could explain non-responsiveness to immune checkpoint inhibitors in patients with DNA mismatch repair-deficient tumors. To test this hypothesis we will make use of three work packages: Workpackage 1: Human DNA mismatch repair-deficient tumors will be analyzed for the spatial localization and organization of collagen fibers, CAF and T-cells and data will be correlated with clinicopathological parameters. Workpackage 2: Patient-derived CAF will be treated with FGFR/PDGFR inhibitors or FAP inhibitors and outcomes such as (neo)matrix deposition, collagen rearrangement, and contractility will be evaluated and the consequent functional impact on T-cell chemotaxis, proliferation and differentiation will be tested. Workpackage 3: Syngeneic mouse tumor models will be used to evaluate if CAF targeting may improve efficacy of immune checkpoint inhibitors (such as anti-PD-1). We anticipate that CAF targeting combined with immunotherapy will synergistically induce and sustain the anti-tumor immune response, resulting in durable tumor regression in a larger population. Encouraging data in the preclinical study will enable fast translation into a clinical phase I/II trial.

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Research team(s)

Progress novel assets (one FIH start) for nontubercular mycobacteria that may act synergistically with bedaquiline and cytochrome bc drugs (RespiriNTM). 01/05/2019 - 30/04/2025

Abstract

Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. Finally, we will also target host-factors that are essential for the intracellular survival of NTM. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

Researcher(s)

Research team(s)

Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors (RespiriTB). 01/05/2019 - 30/04/2025

Abstract

Despite recent progress in biomedical research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is still the world's leading infectious disease killer worldwide. Treatment options are limited, and expensive, recommended medicines are not always available in many countries, and patients experience many adverse effects from the drugs. Thus, there is an acute need for the development of a novel combination regimen with an indication for effective, shorter, and safer treatment of all forms of TB. The overall objective of RESPIRI-TB is to find new drug candidates as potential components of a new, more efficient combination drug regimen against TB that is less prone to resistance and allows shortening of treatment duration for TB, and multidrug-resistant TB. Such a drug combination will synergistically target the energy metabolism of Mtb or complementary targets. To achieve this, we will advance recently discovered inhibitors of the Mtb respiratory pathway. In addition, we will target the Mtb specific molecular mechanism that reduces reactive oxygen species in the cell.

Researcher(s)

Research team(s)

Validation of the oxadiazolone isostere as a carboxylate replacement in caspase inhibitors: approaches involving Strecker-based synthetic methodology development and on-target strategies. 01/10/2018 - 30/09/2021

Abstract

Caspases are intracellular, aspartate selective cysteine proteases. Given their central role in cell death and inflammation, caspases have been studied intensively as drug targets to date. In spite of impressive preclinical results and significant investment in clinical evaluation, no caspase inhibitors have so far been approved as drugs by FDA or EMA. Two important reasons therefore are commonly cited: (1) The large structural homology of caspases that complicates the identification of selective compounds. (2) The limited biopharmaceutical quality of most compounds. Many contain an irreversible covalent warhead function that can potentially induce off-target effects. Most inhibitor families also contain a free carboxylate. Both the ionic character of this group and its potential for toxic metabolite formation, most probably discount critically on the permeability and ADME-Tox properties of inhibitors. Preliminary work at UAMC has identified the oxadiazolone moiety as a useful isosteric replacement for carboxylates in caspase inhibitors. Research in this proposal will validate this finding by introducing an oxadiazolone group in several relevant classes of caspase inhibitors. In addition, synthetic methodology based on the Strecker reaction will be elaborated. The latter will allow efficient access to caspase inhibitors with less reactive warhead types. Finally, drug discovery methodology will be developed that should allow "on-target" synthesis using caspase 1 as a model.

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Research team(s)

Synthesis of inhibitors and inhibitor-derived imaging probes for prolyl oligopeptidase (PREP) and dipeptidyl-peptidase (DPP9) with potential application in neurodegenerative disease. 01/01/2018 - 31/12/2021

Abstract

Prolyl oligopeptidase (PREP) and dipeptidyl-peptidase 9 (DPP9) are two related serine proteases. PREP is mainly expressed in the central nervous system. This proposal will focus on the possibility to inhibit aggregation of alpha-synuclein (alphaSYN) using active-site directed inhibitors of PREP. alphaSYN plays a key role in the pathophysiologies of Parkinson's and related diseases, where aggregates of alphaSYN precipitate as neurotoxic Lewy-bodies. There are currently no PREPinhibitors that are optimized to block alphaSYN aggregation and that have a biological profile that allows drug development. The proposal will therefore deliver optimized PREP inhibitors. In addition, a PREP-targeting imaging probe will be delivered to image (alphaSYN) in the brain. DPP9 has a wider expression in the human body than PREP, and is also present in the human brain. DPP9 is strongly linked to inflammatory processes, also in the context of neuro-inflammation. The latter is present in nearly all neurodegenerative diseases, including in synucleinopathies and Alzheimer's disease. It is also an early marker of disease that is present before symptoms appear. Of note, there are currently no selective DPP9 inhibitors available. Availability of the latter is essential to obtain preclinical validation of DPP9 inhibitors as novel agents that target neurodegeneration. In addition, the project aims to deliver a DPP9-selective probe for use in neurodegenerative disease imaging.

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Research team(s)

Molecular mechanisms of cellular Death and Life decisions in Inflammation, Degeneration and Infection (MODEL-IDE). 01/01/2018 - 31/12/2021

Abstract

The research program on Molecular mechanisms of cellular DEath and Life decisions in Inflammation, Degeneration and Infection (MODEL-IDI) aims at performing fundamental research on the biology of cell death modalities, cell survival regulation and their consequences on the onset and/or progression of diseases. The program aims at linking the discoveries obtained in vitro on the molecular regulation of cell death and inflammation to their in vivo physiological relevance by making use of chemical tool compounds and experimental models of diseases, such as diabetes type I & II, hepatotoxicity and liver cancer, atherosclerosis and neurodegenerative diseases.

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Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds. 01/01/2018 - 31/12/2021

Abstract

Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Necrotic cell death is a kind of cell death in which cells release their cellular content in the surrounding tissue, in contrast to apoptotic cell death. We now realize that multiple forms of regulated necrosis exist. A new type of regulated necrosis that is catalysed by iron was recently unravelled and is now referred to as ferroptosis. Several hereditary conditions have been found that perturb body iron homeostasis and promote pathological deposition of the metal resulting in organ damage in liver, heart, pancreas, thyroid and the central nervous system. For this reason, iron chelators have been implemented or proposed as treatments for these diseases. Because iron is an essential metal for the overall functioning of organisms, whole body scavenging of iron is not preferable due to its expected detrimental side effects. In view of the recent experimental findings that inhibitors of ferroptosis (called ferrostatins) can protect against degenerative diseases, we want to unravel the molecular mechanisms involved in ferroptosis in more detail, identify new ferroptosis inhibitors that can be used in vivo, and validate them in cellular assays and mouse models.

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Research team(s)

Integrated Training in Dry Eye Disease Drug Development (IT-DED3). 01/01/2018 - 31/12/2021

Abstract

The European network for Integrated Training in Dry Eye Disease Drug Development (IT-DED3) aims to deliver multidisciplinary and entrepreneurial researchers trained to develop new therapies for patients suffering from dry eye diseases (DED). DED is a chronic, multifactorial disease of the ocular surface and is a major and increasing healthcare problem due to its high prevalence and economic burden because of the ageing population and frequent computer/tablet/smartphone usage. New DED drug development and translation from "bench to bedside" is urgently needed and therefore IT-DED3 integrates worldclass expertise in medicinal chemistry, process chemistry, ocular drug delivery and formulation, DED models, imaging, biomarker research and clinical ophthalmology. The scientific novelty is manifold, including new drug targets and compound classes, innovative formulation strategies for ocular drug delivery, and novel optical and molecular biomarkers identified by new imaging techniques and genomic-based systematic screening of a database of DED patients. The consortium of 7 beneficiaries and 10 partners (in total 7 from the non-academic sector) from 8 different European countries will select 12 early stage researchers (ESRs). Each ESR will perform high level scientific research in this stimulating multidisciplinary, international and intersectoral environment. Besides the scientific skills, the Personal Career Development Plan (PCDP) of each ESR will include transferable skills such as data management, project and time management, communication and dissemination, IP and valorisation. Both the research and training programme of IT-DED3 will deliver researchers with an enhanced career perspective and employability, who know how to use their entrepreneurial skills to move drug development projects in DED and other fields to the next technology readiness level.

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Computational investigations of the catalytic mechanism of Staphylococcus aureus transglycosylase: design and chemical synthesis of novel mechanism-based inhibitors. 01/10/2017 - 30/09/2021

Abstract

Bacterial resistance against current medications is a growing problem that will pose significant health problems in the near future. Penicillins are a class of antibiotics that exert there effect by blocking the biosynthesis of the bacterial cell wall by means of inhibition of the transpeptidase protein, an enzyme responsible for the synthesis of the essential glycan chains in the cell wall. An alternative approach to inhibit the growth of the bacterial cell wall would be by inhibition of the transglycosylase enzyme, a protein involved in the polymerisation of the sugar chains that make up the backbone of these glycan chains. Currently there are no medications on the market or in clinical trials that have a mechanism of action of glycosyltransferase inhibition, but it has been shown that blocking the normal function of this enzyme leads to inhibition of bacterial cell growth. The main objective of the current project is to identify potent inhibitors against this transglycosylase enzyme using large-scale molecular dynamics simulations to study the catalytic mechanism of action and kinetics in large detail. Results of these simulations will be used to propose novel chemical compounds that will be synthesized through a collaboration with the University of Leuven. Biochemical testing of the antibacterial effects of these compounds will be performed at the University of Liège.

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Past projects

Biopharmaceutical optimization of PET-diagnostic tools targeting fibroblast activation protein (FAP). 01/05/2020 - 30/04/2021

Abstract

Fibroblast activation protein (FAP) is a serine type protease that is expressed on stromal cells of > 90% of all epithelial cancer types, and also in pathological lesions associated with other diseases characterized by tissue remodeling. It is virtually absent in healthy adult tissues. FAP is being studied both as a therapeutic target and a biomarker/diagnostics target: not only in oncology, but also in, e.g., different fibrosis types and cardiovascular disease. UAntwerp has an approved patent for the only highly potent, selective and orally bioavailable small molecule inhibitors of FAP known to date (US9346814 and EP2804859). One of the compounds in this patent (UAMC1110) receives widespread attention as a potential therapeutic and as the structural basis for diagnostic probes. Also at UAntwerp, research is ongoing that aims at producing UAMC1110 derivatives, with main applications in the diagnostics field. A VLAIO-funded O&O project was recently initiated with HistoGeneX, under which fluorescent and colorigenic UAMC1110 derivatives are used to characterize oncology biopsy samples. The applicants of this project now want to apply their expertise in the domain of FAP ligand design for the discovery of new, FAP-targeting PET probes that can be used in diagnostics.

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Development of novel TCO probes for pretargeted intracellular PET imaging. 01/10/2018 - 31/10/2019

Abstract

Radiolabeling of monoclonal antibodies (mAbs) is a powerful preclinical and clinical research tool that finds applications in diagnostic as well as in prognostic and therapeutic settings. Positron Emission Tomography (PET) differs from traditional imaging in that probes known as radiotracers carrying a radioisotope are used to visualize, characterize, and quantify biological processes in vivo. However, despite their attractive properties radiolabeled mAbs have a few important shortcomings. One of the most critical ones is their long circulation time in the body associated with low target to non-target ratios, thus requiring the use of long lived isotopes which yields high radiation dose to the patient. A solution for this problem is offered by pretargeting based on bioorthogonal chemistry. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs are internalized upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims at developing a pretargeted intracellular PET imaging strategy. We will develop novel fluorinated trans-cyclooctene analogues (TCOs) and characterize their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

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Preclinical characterization and biopharmaceutical optimization of the autophagy inhibitor UAMC-2526 for oncotherapy. 01/01/2018 - 31/12/2020

Abstract

Three UAntwerp research groups (Medicinal Chemistry, Physiopharmacology, MIPRO) recently joined forces for the discovery and study of autophagy modulators as potential oncology therapeutics. Hitherto, this approach has resulted in a joint patent application and several manuscripts that have either been published or are under preparation. Most attention to date has gone to investigation of UAMC-2526, an Atg4B-targeting autophagy inhibitor that was discovered by the project team. This compound has potent in vivo autophagy blocking properties and significant anti-tumoral potential in an in vivo xenograft mouse model of colorectal cancer. To ensure economical valorization interest for UAMC-2526 and the UAntwerp-patented family of compounds to which it belongs, more basic research is required. The balanced package of medicinal chemistry, in vitro pharmacology and in vivo oncology that is presented here, should provide detailed insight in the potential of UAMC-2526 and its analogues as a potential therapeutic agent. In addition, biopharmaceutically optimized follow-up candidates for UAMC-2526 will be delivered. At the same time, this effort will increase the compounds' attractiveness to external economic valorization partners. Finally, this project will also create critical mass for a preclinical research platform on autophagy research at UAntwerp. This platform will unite chemical and biological capabilities in autophagy research that will be highly instrumental to support research programs, but will also be offered to private partners that require expertise in the domain.

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Inhibitors of prolyl oligopeptidase (PREP) as novel candidates for tackling synucleinopathies: insight in structural, thermodynamic and kinetic parameters that determine inhibitor potential to block PREP-promoted alpha-Synuclein aggregation 01/10/2017 - 30/09/2020

Abstract

Inadequate perfusion, oxygen limitation and cell metabolic changes, are key factors contributing to the formation of an acidic microenvironment in tumors.1 Two pivotal adaptations of tumor cells, related to maintaining intracellular pH and homeostasis in an acidic environment, have recently received significant attention: (1) the presence of chronic autophagy and (2) the overexpression of carbonic anhydrases (CAs), mainly CA IX and CA XII. Aiming to counter these essential tumor survival processes, the proposal deals with discovering and thoroughly evaluating novel autophagy inhibitors and and dual [autophagy-CA] inhibitors. The following three Work Packages will be elaborated during the course of the project: 1) Biopharmaceutical optimization of the host's Atg4B-inhibitor set. 2) Design and synthesis of dual [Atg4B-CA] inhibitors. 3) Biological characterization of Atg4B- and hybrid [Atg4B-CA] inhibitors in acidic cancer cell cultures and in an animal model of colorectal cancer.

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TRP channel sensitization as target for treatment of hypersensitivity (TRP-sensation). 01/07/2017 - 30/06/2021

Abstract

IBS affects around 18% of the general population. It is one of the most common disorders seen by physicians. However, the IBS market is commercially weak due to the limited understanding of its pathophysiology and the availability of limited treatment options. In fact, IBS is largely seen as a syndrome rather than a disease. By increasing the understanding of the underlying mechanisms of IBS coupled to validation of therapeutic and diagnostic targets, we have the ambition to turn IBS "from a syndrome into a disease". To achieve this, we want to establish an academic knowledge platform and an industrial network in Flanders that is able to tackle the major challenges in the IBS field, to identify and validate novel therapeutic and diagnostic targets and to develop them into novel therapeutic and diagnostic solutions. When available, this network will put Flanders at the forefront of innovation in the emerging IBS field.

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Novel Atg4B-inhibitors and dual [Atg4B-carbonic anhydrase] inhibitors for interfering with cytoprotective mechanisms of cancer cells in the acidic tumor micro-environment (ONCOPHAGY). 01/04/2017 - 31/03/2019

Abstract

The microenvironment of most solid tumors tends to be significantly more acidic than healthy tissue. Inadequate perfusion, oxygen limitation and cell metabolic changes, are key causative factors for this situation. The acidic pH induces a number of specific genetic, transcriptional and metabolic effects in tumor cells. These are required for survival under increased H+- stress. Evidence is now mounting that these effects also play a major role in tumor progression, invasiveness and the development of multi-resistance to therapy. Two pivotal adaptations related to maintaining intracellular pH homeostasis in an acidic environment, have recently received significant attention: (1) the presence of chronic autophagy in tumors and (2) the overexpression of carbonic anhydrases (CAs), mainly CA IX and CA XII. This project will biopharmaceutically optimize a novel class of specific autophagy inhibitors that target Atg4B. The specific goal of this part of the project is to obtain orally bioavailable and metabolically stable compounds that are fit for in vivo applications. The relevance of these compounds is clear, given the unmet demand for reliable, specific inhibitors in the domain of autophagy. At the same time, the project will evaluate the potential for therapy development of the compounds in the framework of cancer. Finally, the proposal will explore whether a further increase of anti-tumor efficiency can be obtained by combining Atg4B- and CA-inhibitor pharmacophores in a single compound.

Researcher(s)

Research team(s)

Target-guided synthesis (TGS) of enzyme inhibitors via a two-component cyclocondensation using urokinase plasminogen activator (uPA) as a model target. 01/04/2017 - 31/03/2018

Abstract

Common to all contemporary drug discovery strategies is that they revolve around iterative cycles of design, synthesis and potency evaluation, each time producing further optimized compounds. This is generally a very time- and cost-consuming process that could be significantly shortened by implementing so-called target-guided synthesis (TGS). The latter relies on direct assistance of the drug target, which serves as a physical template that selects useful drug fragments and assembles them into finalized ligands. In this way, synthesis and potency determination, along with aspects of molecular design, are merged into a single, time-efficient experimental step. Over the last 15 years, limited but compelling proof-of-concept for TGS has been reported in literature. Nonetheless, in order to increase the practical value of target-guided approaches for drug discovery, further exploration of bio-orthogonal chemistry amenable to TGS is needed. In this context, a recently disclosed cyclocondensation of 2-hydrazinopyridines with aldehydes yielding triazolopyridines has drawn our attention. Interestingly, the triazolopyridines obtained from this protocol bear strong structural similarity to imidazopyridines. Derivatives of the latter scaffold have been recently reported by our group as potent inhibitors of urokinase. However, given their more straightforward preparation via a two-component reaction, triazolopyridines are now considered as potentially interesting motifs for TGS of uPA inhibitors. This project aims to extend the current state of art by (1) expanding the limited range of chemistry types amenable to TGS by introducting a novel target-guided two-component cyclization reaction, giving rise to (2) new triazolopyridine-based uPA inhibitors. In addition, (3) computational approaches will be developed to model and rationalize the outcome of the target-guided strategy. As the model target for this project has been selected urokinase plasminogen activator (uPA), a daunting but highly promising drug target. The potential to deliver novel druglike, low nanomolar inhibitors of uPA will be used to assess the value of the target-guided approaches. Given the status of uPA as a validated oncology target, novel inhibitors of this enzyme have significant value for drug discovery.

Researcher(s)

  • Promotor: Gladysz Rafaela

Research team(s)

High-end molecular dynamics simulations combined with click chemistry synthesis to develop novel therapeutic compounds starting from small molecule fragments. 01/04/2017 - 31/03/2018

Abstract

Within the molecular modeling research group with UAMC we are evaluating and developing a number of computational approaches to design - in a de novo manner - novel small molecules with pharmacological properties. One such approach is the use of high-throughput molecular dynamics (MD) at atomic resolution and with the inclusion of explicit solvent. With this approach, the potential binding of small fragments towards therapeutic relevant proteins is explored using MD simulations at long timescales. The here presented project explores the potential benefits of combining experimental methods with in silico approaches, in casu the combination of click chemistry technologies with advanced molecular dynamics simulations of the movement and interactions of small fragments located in close proximity to a therapeutic protein of interest. Hence, extensive synthetic chemistry, internal biochemical testing and the combination of advanced molecular dynamics with molecular stereographics will be the main ingredients to a successful completion of this project.

Researcher(s)

Research team(s)

On-target assembly of druglike small molecules as protease inhibitors: a bottom-up approach using urokinase plasminogen activator (uPA) as a model target. 01/10/2016 - 30/09/2019

Abstract

Common to all contemporary drug discovery strategies is that they revolve around iterative cycles of design, synthesis and potency evaluation, each time producing further optimized compounds. This is generally a very time- and cost-consuming process that could be significantly shortened by implementing so-called "on-target" strategies. The latter rely on direct assistance of the drug target, which serves as a physical template that selects useful drug fragments and assembles them into finalized ligands. In this way, synthesis and potency determination, along with aspects of molecular design, are merged into a single, time-efficient experimental step. This project aims to (1) expand the limited range of chemistry types that are currently known to be amenable to on-target approaches, (2) focusing on reactions that deliver "druglike" molecules. (3) In addition, computational models offering insight at the molecular level in on-target reactions will be developed to rationalize and refine the experimental approaches. As the model target for this project has been selected urokinase plasminogen activator (uPA), a daunting but highly promising drug target. The potential to deliver novel druglike, low nanomolar inhibitors of uPA will be used to assess the value of the on-target approaches. Given the status of uPA as a validated drug target, novel inhibitors of this enzyme have significant value for drug discovery.

Researcher(s)

Research team(s)

Validation of the oxadiazolone isostere as a carboxylate replacement in caspase inhibitors: approaches involving Strecker-based synthetic methodology development and on-target strategies. 01/10/2016 - 30/09/2018

Abstract

Caspases are intracellular, aspartate selective cysteine proteases. Given their central role in cell death and inflammation, caspases have been studied intensively as drug targets to date. In spite of impressive preclinical results and significant investment in clinical evaluation, no caspase inhibitors have so far been approved as drugs by FDA or EMA. Two important reasons therefore are commonly cited: (1) The large structural homology of caspases that complicates the identification of selective compounds. (2) The limited biopharmaceutical quality of most compounds. Many contain an irreversible covalent warhead function that can potentially induce off-target effects. Most inhibitor families also contain a free carboxylate. Both the ionic character of this group and its potential for toxic metabolite formation, most probably discount critically on the permeability and ADME-Tox properties of inhibitors. Preliminary work at UAMC has identified the oxadiazolone moiety as a useful isosteric replacement for carboxylates in caspase inhibitors. Research in this proposal will validate this finding by introducing an oxadiazolone group in several relevant classes of caspase inhibitors. In addition, synthetic methodology based on the Strecker reaction will be elaborated. The latter will allow efficient access to caspase inhibitors with less reactive warhead types. Finally, drug discovery methodology will be developed that should allow "on-target" synthesis using caspase 1 as a model.

Researcher(s)

Research team(s)

Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. 01/10/2016 - 30/09/2018

Abstract

The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and innovative treatment opportunities in diseases linked with inflammation and necrotic cell death.

Researcher(s)

Research team(s)

Hit-to lead and lead optimization approaches in Mycobacterium tuberculosis drug-discovery. 15/07/2016 - 14/07/2017

Abstract

This DOCPRO1-project is intended to supplement the three year fellowship of Olga Balabon, a Marie Curie PhD fellow in the ITN-EID network "OpenMedChem". OpenMedChem project is open innovation collaboration between the laboratory of Medicinal Chemistry at UA and a major industrial Research&Development unit of GlaxoSmithKline (GSK I+D, Tres Cantos, Spain). OpenMedChem focuses on discovery of novel anti-tuberculosis drug candidates. Despite the existence of treatments for tuberculosis (TB), the threat it represents is still a painful reality for the nearly nine million people infected, and the one and a half million that die each year. The disease also represents an escalating threat for global health, with the increasing prevalence of multi-drug resistant (MDR) TB strains, which are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin - and extensively-drug resistant (XDR) TB that are also resistant to three or more of the six classes of second-line drugs. In an unprecedented move in line with the Open Innovation paradigm, GSK shared with the University of Antwerp its anti-mycobacterial High-Throughput-Screening (HTS) campaign results of over 2 million druglike compounds tested against M.tb. Initial research in this project consisted of a bioinformatics compound clustering into families with promising antitubercular properties. The most promising families were selected for further investigation within the project. Fellow Olga Balabon started with investigating chemical space around a class dihydrotriazines, containing a typical dihydrofolate reductase pharmacophore. Scaffold hopping and decoration delivered a substantial set of novel compounds. Nonetheless, cytotoxicity issues and limitations were decisive to abandon this class of molecules. Instead, Olga is currently working on a class of hydantoin antitubercular compounds that have been identified by GSK as inhibitors of the mycobacterial target decaprenyl-phosphoryl-d-ribose oxidase (DprE1). DprE1 is a recently validated promising mycobacterial drug target. The research during the running time of the DOCPRO1-project aims at in-depth SAR investigation of the substitution pattern on the hydantoin-based DprE1 inhibitors. In addition, a series of hydantoin analogues containing a central pyrrolidine ring, will be explored. Finally, hybrid compounds will be synthesized that consist of complementary fragments of the hydantoin-based DprE1 inhibitors and a previously reported very potent inhibitor (TCA1).

Researcher(s)

Research team(s)

On-target assembly of druglike small molecules: a bottom-up approach using urokinase plasminogen activator and caspase 1 as model targets. 01/01/2016 - 31/12/2019

Abstract

1) Current status in drug discovery methodology There are four commonly used approaches for the generation of "hits" and "leads" in contemporary drug discovery: (1) Structure-Activity-Relationship (SAR) research on high throughput screening (HTS) data, (2) transformation of endogenous ligands into druglike compounds, (3) in silico drug design and (4) fragment-based design. Due to the absence of a single eminent strategy, drug discovery projects often try implementing tailored aspects of several of these approaches simultaneously. Common to all these approaches is that lead molecules are produced from iterative cycles of design, synthesis and potency evaluation, each time producing further optimized compounds. This is generally a very time- and cost-consuming process that could be significantly shortened by implementing "on-target" strategies. The latter rely on direct assistance of the drug target, which serves as a physical template that selects useful drug fragments and assembles them into finalized ligands. In this way, synthesis and potency determination, along with aspects of molecular design, are merged into a single, time-efficient experimental step. Limited but convincing proof for the "on-target" drug design concept is present in literature and has relied on "click chemistry", reductive amination, hydrazone formation and disulfide exchange.1 In order to increase the practical value of on-target approaches for drug discovery, three factors are in our opinion required: (1) expansion of the range of (bio-orthogonal) chemistry types amenable to on-target approaches and, related to the former, (2) improvement of the "druglikeness" of the compound types that can be produced. (3) In addition, models offering insight into the fundamental kinetic and thermodynamic drivers of "on-target" reactions are, apart from one example, virtually absent from the scientific literature.2 2) Current status in drug discovery for urokinase plasminogen activator (uPA) and caspase 1. uPA and caspase 1 have been selected as the model targets for this work. Longstanding expertise in inhibitor discovery and biochemical screening exists for these targets at UAMC. In addition, both are generally considered as "daunting targets" for which drug discovery has proven challenging. uPA is a trypsin-like serine protease that is overexpressed in metastasizing solid tumors. The enzyme is a valuable oncology target but clinical development of its inhibitors has been problematic. This is most probably related to the doubtful biopharmaceutical quality of developed compounds and their insufficient selectivity with respect to other, phylogenetically related trypsin-like proteases.3 Likewise, selectivity issues have also been a constant concern with caspase 1 inhibitors. Caspase 1, also known as interleukin 1 converting enzyme (ICE) is a cysteine protease and a so-called "inflammatory caspase". Given its involvement in inflammasome formation, pyroptosis and necrosis, ICE is a validated drug target for a range of disorders characterized by inflammation and tissue remodeling. 4 B) Project Objectives 1) Developing reliable on-target versions of reaction types with high value for drug discovery. 2) Developing computational approaches to model and rationalize on-target reactions and their outcome. 3) Validating the technology by producing druglike inhibitors for uPA and caspase 1.

Researcher(s)

Research team(s)

Rational design and synthesis of antagonists of the TSLP complex using chemo- and bioinformatics approaches. 01/01/2016 - 04/11/2018

Abstract

TSLP (thymic stromal lymphopoietin) is a pro-inflammatoir cytokine produced by the epithelial cells. It binds to its receptor called TSLPR. This project aims at developing a number of novel inhibitors which block the complexation of TSLP and TSLPR, using bio- en chemo-informatic tools.

Researcher(s)

Research team(s)

"Hit-to-lead" optimization and biological characterization of novel anti-mycobacterials. 15/07/2015 - 14/07/2016

Abstract

This DOCPRO1-project is intended to supplement the three year fellowship of Maciej Rogacki, a Marie Curie PhD fellow in the ITN-EID project "OpenMedChem". "OpenMedChem" is an open innovation collaboration between the laboratory of Medicinal Chemistry at UA and the R&D-site of Glaxo-Smith-Kline in Tres Cantos (Spain). OpenMedChem focuses on discovery of novel anti-tuberculosis (TB) drug candidates. Despite the existence of treatments for TB, the threat it represents is still a painful reality for the nearly nine million people infected, and the one and a half million that die, each year. The disease also represents an escalating threat for global health, with the increasing prevalence of Multi Drug Resistant (MDR) TB strains that are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin - and Extremely Drug Resistant (XDR) TB strains that are also resistant to three or more of the six classes of second-line drugs. In an unprecedented move in line with the Open Innovation paradigm, GSK has shared with the University of Antwerp, its anti-mycobacterial High-Throughput-Screening data of over 2 million druglike compounds. Initial research in this project consisted of a bioinformatics compound clustering into families with promising antitubercular properties. The most interesting families were subsequently investigated further in depth. Maciej Rogacki first investigated chemical space around a class of (pyridin-2-yl)azahetarylamines. Scaffold hopping and decoration resulted in novel compounds with nanomolar antimycobacterial potency (MIC). Nonetheless, toxicity issues were decisive to leave this class of molecules. As an alternative, Maciej is currently working on a class of hydantoin antitubercular compounds that have been identified by GSK as inhibitors of decaprenyl-phosphoryl-d-ribose oxidase (DprE1), a validated mycobacterial drug target. Research during the running time of the DOCPRO1-project would aim at continuing the in-depth structural exploration of this class of hydantoins. New Scaffold Hopping strategies will also be investigated to evaluate how the central hydantoin building block in these compounds can be replaced.

Researcher(s)

Research team(s)

Project website

Synthesis and evaluation of radioligands for PDE7 imaging in addiction animal model 01/02/2015 - 31/12/2015

Abstract

Recently, the mechanism of action of phosphodiesterase 7 (PDE7) inhibitors to fight addiction in humans was elucidated. In the literature, there are no radiotracers for PDE7 imaging. At UAMC, we synthesized 8 potent PDE7 inhibitors. The most potent compounds will be labeled with 11C and evaluated in vivo to determine if they are suitable to quantify PDE7 in the brain and also injected in an addiction rat model.

Researcher(s)

  • Promotor: Thomae David

Research team(s)

Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2015 - 31/12/2020

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

Research team(s)

The Extracellular Matrix in Epileptogenesis (ECMED). 01/01/2015 - 31/12/2018

Abstract

This project brings together considerable expertise from academic and industry partners in the biology of the extracellular matrix (ECM) with experts in epilepsy research. This, therefore, represents a truly collaborative effort to determine not only the role of the ECM in the development of epilepsy but also novel approaches to treat and to prevent epilepsy.

Researcher(s)

Research team(s)

Synthesis and characterization of molecular imaging probes for fibroblast activation protein (FAP), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase 8 (DPP8), derived from selective inhibitors. 01/01/2015 - 31/12/2018

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Optimization of novel lead compounds for the treatment of African trypanosomiasis using innovative medicinal chemistry and formulation. 01/01/2015 - 31/12/2018

Abstract

The main objective of this research project is the lead optimization of the identified triazine series using medicinal chemistry and formulation technologies to increase the in vivo activity against T. brucei by combining enhanced solubility and metabolic stability with enhanced drug delivery.

Researcher(s)

Research team(s)

Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets (INTEGRATE). 01/01/2015 - 31/12/2018

Abstract

The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure will be accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. Our intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.

Researcher(s)

Research team(s)

Design, Synthesis and evaluation of new potent radioligands for PDE7 imaging in the brain and implication of PDE7 in neurological disorders. 01/01/2015 - 16/02/2016

Abstract

The main objective of this project is to develop a suitable PET radiotracer for PDE7 imaging. We have synthesized 6 potent PDE7A inhibitors based on the spiroquinazolines scaffold (Figure 2). Potency of the compounds (low nanomolar PDE7A and PDE7B IC50) and selectivity towards other PDE are essential properties for a PDE7 radiotracer. These properties will be tested by Omeros (Seattle, WA, USA) before the beginning of the project and will allow us to rank the compounds to be evaluated in vivo.

Researcher(s)

  • Promotor: Thomae David

Research team(s)

Design and synthesis of TSLP complex antagonists based on chemo- and bio-informatics. 01/01/2015 - 31/12/2015

Abstract

Atopic diseases represent an important unmet need in modern day medicine. The pro-inflammatory cytokine TSLP is a key player in these pathologies. The aim of this project is the development of small molecules capable of disrupting TSLP signalling, using a chemo-and bio-informatics approach. These small molecules could help elucidate the role of TSLP in various pathologies and could be a starting point for further development of drugs targeting this pathway.

Researcher(s)

Research team(s)

Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. 01/10/2014 - 30/09/2016

Abstract

The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and innovative treatment opportunities in diseases linked with inflammation and necrotic cell death.

Researcher(s)

Research team(s)

An in-silico-based virtual screening of the compounds. 16/08/2014 - 16/09/2014

Abstract

This project represents a formal service agreement between UA and on the other hand VIB. UA provides VIB research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD). 01/03/2014 - 28/02/2018

Abstract

This project aims to unite global efforts to target the highly druggable class of enzymes called cyclic nucleotide phosphodiesterases (PDEs) in the fight for neglected parasitic diseases (NPD). It will establish a drug discovery platform, PDE4NPD, that combines phenotypic screening with efficient target-centric drug discovery, including target validation, various strategies for compound screening, PDE hit and lead optimization, safety and toxicology assessments and evaluation of anti-parasitic activity.

Researcher(s)

Research team(s)

Serthera: locking and monitoring of serine protease activity as the technological base for development of new and innovative drug candidates. 01/06/2013 - 31/08/2014

Abstract

The overall aim is to build expertise in the domain of inhibitor and probe development with a focus on serine proteases. The academic platform will establish collaborations with academic and industrial partners. The project will lead to the generation of knowledge in the domain.

Researcher(s)

Research team(s)

Design, synthesis and evaluation of new potent radioligands for PDE7 imaging in the brain. 01/02/2013 - 31/12/2013

Abstract

Cyclic adenosine 3',5'-monophosphate (cAMP) is an intracellular second messenger and is implicated in many signal transductions like hormonal and neurotransmitter stimulation. Among the eleven families of phosphodiesterases (PDEs), PDE7 hydrolyses specifically cAMP and regulates intracellular concentration of this second messenger. Because of the important role of cAMP, PDE7 is a therapeutic target for treating central nervous system disorders like Alzheimer's, Parkinson's, and Huntington's disease. are currently investigating the impact of PDE7 inhibitors in CNS related diseases. In vivo imaging using Positron Emission Tomography (PET) is a powerful tool to monitor the stages of disease, to study human human physiology and metabolism, to investigate in vivo the properties of new drugs in (pre)clinical trials. This technique is quantitative and very sensitive and it is a non invasive technique which is a major advantage in brain imaging. Radiotracers are investigated to image in vivo biological targets like a receptor, an enzyme or a tissue (e.g. tumor). In the literature, there are no radiotracers described for PDE7 imaging. Based on the existing molecules for PDE7 inhibition, we will synthesize new compounds and label them with 11C. The new radiotracers will be injected in vivo in mice to determine if they are suitable to quantify PDE7 in the brain.

Researcher(s)

  • Promotor: Thomae David

Research team(s)

PET and SPECT imaging of protease activity by activitybased probes. 01/01/2013 - 31/12/2016

Abstract

The main objective of this research proposal is the development of a methodology for PET and SPECT imaging of the enzymatic activity of serine and cysteine proteases using a pretargeting approach with specific activity-based probes and bioorthogonal ligation with radiolabels.

Researcher(s)

Research team(s)

Identification, lead optimization and validation of necroptosis inhibitors. 01/01/2013 - 31/12/2016

Abstract

In this project we want to identify novel necroptosis inhibitors by performing a compound screen using a biochemical assay and a cellular assay (mouse and human) for TNF-induced necroptosis. In addition, we will also try to synthesize specific RIPK1 and RIPK3 targeting the ATP-binding pocket.

Researcher(s)

Research team(s)

Activity-based probes for PET imaging of protease activity. 01/01/2013 - 31/12/2016

Abstract

Proteases are important drug targets and show increasing application as biomarkers for several diseases. Non-invasive imaging of their proteolytic activity status in vivo offers tremendous potential. We will develop activity-based imaging probes targeting proteases with relevance in oncology and inflammation. These probes will be used in a two-step approach in which the pretargeting step is followed by bioorthogonal ligation with a PET label.

Researcher(s)

Research team(s)

Medicinal chemistry open innovation doctorates (OpenMedChem). 01/10/2012 - 30/09/2016

Abstract

In this context, neglected diseases research and development is opening important new avenues of collaboration between academia and industry. The scientific focus of this EID project will be on the design and synthesis of novel antituberculosis drugs. The fellows will have unique access to corporate HTS screening hits while being exposed to both industrial and academic med chem strategies and philosophies. These chemical efforts will be supported by the application of advanced new secondary biological assays for compound evaluation. For example, the fellows will be exposed to cutting edge microfluidics techniques to allow for in depth study of the activities of the new compounds and to provide a platform for investigating the gross modes of action of both novel and known antituberculars.

Researcher(s)

Research team(s)

Active Center-Asisted Selection and Assembly (ACASA): a bottom-up approach to druglike protease inhibitors using caspase 4 as a model target. 01/10/2012 - 30/09/2016

Abstract

This proposal aims at developing an innovative, robust and time/cost-effective methodology with general applicability in the field of protease inhibitor research. As such, it projects the production of target compounds with a non-peptidic architecture consisting of a central, rigid scaffold decorated with substituents that are accomodated in the S- and/or S'-pockets of a target protease. The proposal's approach differs fundamentally from existing methodologies in its systematic investigation and implementation of target-assisted selection and assembly strategies. The validity of the basic inceptions underlying the approach will be assessed by applying it for the production of druglike inhibitors for the cysteine protease caspase 4. Caspase 4 is a so-called inflammatory caspase. This group of enzymes is currently the subject of intense research that tries to map their functions and its involvement in a whole series of pathologies. To date, no inhibitors that are selective for this enzyme with respect to the other caspases, have been described. Evidently however the availability of such compounds would be highly desirable, both for applications as a research tool or as potential therapeutics.

Researcher(s)

Research team(s)

Immuno-positron emission tomography as a potential biomarker for diagnosis and treatment in Alzheimer disease. 01/07/2012 - 30/06/2014

Abstract

This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Development and functional characterization of inhibitors targeting specific inflammatory caspases. 01/01/2012 - 31/12/2015

Abstract

The inflammatory caspases (i.e. mouse caspase-1, -11 and -12, and c human caspase-1, 4-, and -5) modulate inflammatory and host defense responses through the secretion of pro-inflammatory cytokines and the induction of pyroptosis, a pro-inflammatory cell death mode that removes infected immune cells and prevents proliferation of microbial pathogens. However, undesired activation of inflammatory caspases is associated with auto-inflammatory disorders in humans. Thus, the availability of specific inhibitors would offer tremendous opportunities for studying the signaling pathways of inflammatory caspases, and for therapeutic intervention. However, the development of inhibitors that can discriminate between different inflammatory caspases is still a major challenge. Here, we propose two complementary approaches to resolve this issue. In a first approach, optimized peptide-based inhibitors of the inflammatory mouse caspases-1, -11 and -12 will be developed based on their protein substrate repertoires identified by positional proteomics. As a second approach, a targeted chemical library based on selected heterocyclic scaffolds will be developed for the identification of non-peptide small molecule inhibitors of the aforementioned caspases. The potency, selectivity and stability of these peptide- and non-peptide inhibitors will be characterized in biochemical assays and in mouse models of inflammatory and infectious diseases.

Researcher(s)

Research team(s)

ChemPro Tools - Development of chemical tools and proteomics methodology for the study fo proteolytic systems. 01/01/2012 - 31/12/2015

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Project website

Active center assisted selection and assembly: a bottom-up approach to druglike protease inhibitors using urokinase plasminogen activator as a model target. 01/01/2012 - 31/12/2015

Abstract

This project aims at developing an innovative, robust and time/cost-effective methodology with general applicability in the field of protease inhibitor research. As such, it projects the production of target compounds with a non-peptidic architecture consisting of a central, rigid scaffold decorated with substituents that are accomodated in the S- and/or S'-pockets of a target protease. The project's approach differs fundamentally from existing methodologies in its systematic investigation and implementation of target-assisted selection and assembly strategies.

Researcher(s)

Research team(s)

Cysteine protease inhibitors for protozoan infections: metacaspases as promising new targets. 01/10/2011 - 31/08/2013

Abstract

Metacaspasen (MCAs) are a new family of cystein proteases found in parasitic protozoa and whom form a valuable new drug target in drug research and development. These proteases are possibly involved in cell death, considered vital for the survival of the parasite and are fundamentally different from the orthologous humane caspases. The objective of this doctorates thesis is the development of powerful and selective inhibitors of the MCA2 of Trypanosoma brucei, with high activity in vitro and low cytotoxicity.

Researcher(s)

Research team(s)

Development of uPA probes as tools for imaging and diagnostic applications. 01/05/2011 - 30/04/2013

Abstract

The aim of this project is to further develop uPA probes, of which we already showed the efficacy in in vitro studies, to be used in cellular and in vivo. The IP of these innovative probes have recently been submitted to the UA interface for patenting. The first step in the valorisation of the probes is to obtain proof of concept in in vivo disease models. In the subsequent phase these results will permit us to obtain further funding from larger public (Fournier-Majoie, IWT) or private (VC) institutions. Our goal is to proceed with spinning-out this te chnology into a company preferentially within 3 years.

Researcher(s)

Research team(s)

Topically applicable long-lasting glucocorticoid receptor agonists for the treatment of inflammatory skin diseases. 15/04/2011 - 14/04/2012

Abstract

This 'proof-of-concept' research is focussed on the development of innovative long-lasting and selective glucocorticoid receptor agonists for the topical treatment of skin inflammation diseases such as atopic dermatitis and psoriasis.

Researcher(s)

Research team(s)

Specific blocking of autophagy processess via inhibition of Atg4B? An approach based on drug-like inhibitors and activity-based probes. 01/01/2011 - 31/12/2014

Abstract

This proposal aims at developing inhibitors of cysteine protease Atg4B, a prime regulator of autophagy, as innovative tools for selective autophagy blocking. Additionally, inhibitor-derived probe molecules will be prepared, enabling further study of Atg4B's role in cellular physiology and in the initiation and propagation of autophagic processes.

Researcher(s)

Research team(s)

Optimization on trypanocidal compounds: An insight on correlation of 'in vitro' and 'in vivo' activity 01/01/2011 - 31/12/2012

Abstract

We aim to investigate why some of our compounds series have a low or no activity in the HIV screen or in the trypanosome in vivo evaluation. A definite answer will be provided by focused studies on the pharmacokinetic profile that will deliver information pivotal to interpret the lower as expected in vitro and in vivo activity of some compound series.

Researcher(s)

  • Promotor: Venkatraj Muthusamy

Research team(s)

Active center assisted selection and assembly: a bottom-up approach to druglike protease inhibitors using urokinase plasminogen activator as a model target. 01/01/2011 - 31/12/2011

Abstract

This project aims at developing an innovative, robust and time/cost-effective methodology with general applicability in the field of protease inhibitor research. As such, it projects the production of target compounds with a non-peptidic architecture consisting of a central, rigid scaffold decorated with substituents that are accomodated in the S- and/or S'-pockets of a target protease. The project's approach differs fundamentally from existing methodologies in its systematic investigation and implementation of target-assisted selection and assembly strategies.

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A fragment-based approach to protease inhibitor development. 01/10/2010 - 30/09/2020

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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Fibroblast Activation Protein (FAP) and cancer: development of inhibitors for the treatment of malignant disease and their use as biomarkers FAP probes. 01/10/2010 - 30/09/2014

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Development of urokinase-type plasminogen activator (uPA) inhibitors as potential drugs in anti-metastatic cancer therapy. 01/10/2010 - 30/09/2012

Abstract

The following 3 goals were put forward at the start of my PhD research. - Development of reversible uPA inhibitors with a similar or increased activity and selectivity compared with irreversible diarylphosphonates - Optimizing the already synthesised diarylphosphonates - Are the uPA inhibitors also useful in other disease models?

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Research team(s)

Combined highly active anti-retroviral microbicides (CHAARM). 01/01/2010 - 30/06/2015

Abstract

The main objective of this project is to develop combinations of highly active specifically-targeted microbicides for vaginal and rectal application. We shall investigate the microbicide potential of protease inhibitors and to test them in combination with inhibitors of HIV-1 reverse transcriptase and/or integrase and/or fusion inhibitors.

Researcher(s)

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From protease inhibitors with increased target residence time to activity-based probes: useful tools in different areas of drug discovery. 01/01/2010 - 31/12/2013

Abstract

In this research project we aim to develop protease inhibitors that have the characteristics to become useful chemical tools in different areas of drug discovery. These tools will have the potential to be used in target discovery and target validation, hit and lead identification, for the identification of off-targets, as biomarkers and in molecular imaging.

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Optimization of the synthesis of diarylphosphonate inhibitors of serin proteases using reaction calorimetry. 01/01/2010 - 31/12/2011

Abstract

The synthesis of diaryl phosphonates, inhibitors of serine proteases, will be optimized and scaled up using reaction calorimetry. The reaction variables that allow for a more efficient Birum-Oleksyszyn reaction, will be identified and studied. In addition, general applicability of results will be assessed during the preparation of a library of potential serine protease inhibitors using a broader spectrum of synthetic substrates.

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Cysteine protease inhibitors for protozoan infections: metacaspases as promising new targets. 01/10/2009 - 30/09/2011

Abstract

Metacaspasen (MCAs) are a new family of cystein proteases found in parasitic protozoa and whom form a valuable new drug target in drug research and development. These proteases are possibly involved in cell death, considered vital for the survival of the parasite and are fundamentally different from the orthologous humane caspases. The objective of this doctorates thesis is the development of powerful and selective inhibitors of the MCA2 of Trypanosoma brucei, with high activity in vitro and low cytotoxicity.

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Development of a click chemistry based synthetic methodology for the synthesis of innovative potential lead compounds and/or chemical probes. 01/10/2009 - 30/09/2010

Abstract

Several projects in the Laboratory for Medicinal Chemistry rely on click chemistry (1) as an essential aspect of bio-orthogonal derivatisation of proteins under physiological conditions or (2) as an efficient tool for the construction of innovative biologically active compounds. The candidate will apply his expertise in this domain to support and develop these ongoing projects. Additionally, novel approaches to overcome current boundaries in the domain of click chemistry will be investigated.

Researcher(s)

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Synthesis of diamino acid derivatives with a cyclopropane or aziridine skeleton and their application in the synthesis of potential physiologically active alpha,gamma-diaminobutyric acid derivatives. 01/01/2009 - 31/12/2012

Abstract

Objectives of the project: - Development and optimization of the stereoselective synthesis of new derivatives of 1,2-diaminocyclopropane-1-carboxylic acid, 2-amino-2-aziridin-2-ylacetic acid and 2-amino-3-aziridin-2-ylpropionic acid. - Development of ring opening reactions of 1,2-diaminocyclopropane-1-carboxylic acid derivatives, 2-amino-2-aziridin-2-ylacetic acid derivatives and 2-amino-3-aziridin-2-ylpropionic acid derivatives towards potentiallyphysiologically active amino acid derivatives among which 2,4-diaminobutyric acid derivatives. - Biological screening of new conformationally constrained diamino acid derivatives and corresponding ring opened compounds.

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Structure elucidation of synthetic compounds and natural products by NMR and LC-NMR spectroscopy. 19/12/2008 - 18/12/2013

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

Research team(s)

Design and synthesis of metacaspase inhibitors as potential lead compounds for antiparasitic chemotherapeutics. 01/10/2008 - 30/09/2010

Abstract

This research evolves around a cysteïne protease of Trypanosoma brucei, metacaspase (MCA), of which the function is currently still unknown. Metacaspase has already been tested as drug target, but no MCA inhibitors are known at present. The project focuses on a rational design and synthesis of inhibitors in order to establish a structure-activity-relationship. In a next step, optimization of the achieved inhibitors will be examined. Our final goal is to develop chemically stable inhibitors with a high potency and maximal selectivity with respect to human caspases.

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FWO-Visiting Postdoctoral Fellowship (Mathusamy Venkatraj, Indië) within the framework of the project "Design, synthesis and evaluation of diverse enzyme inhibitors as potential antiparasitic compounds". 01/11/2007 - 31/10/2008

Abstract

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Research team(s)

Design, synthesis and evaluation of potent and selective inhibitors of prolyl peptidases of clan SC. 01/10/2007 - 30/09/2010

Abstract

Due to the unique structure of proline, relatively few peptidases are able to cleave peptide bonds containing proline. Many biologically active peptides contain an evolutionary conserved proline residue as a proteolytic-processing regulatory element, and therefore proline-specific peptidases are expected to be important 'check-point' controls with great potential as targets for drug discovery. Remarkably, in humans, all enzymes specific for cleaving of a Pro-Xaa bond, are found in clan SC. They share a serine nucleophile and a catalytic triad being in the linear order Ser-Asp-His. This project aims at the development of powerful and selective inhibitors for the catalytically active Pro-Xaa peptidases (DPP IV, DPP II, DPP 8, DPP 9, FAP and POP). Inhibitors will be used primarily for the full functional characterization of the different enzymes and, if possible, for their further validation as therapeutic targets. Inhibitors of DPP IV have been shown to be applicable in the treatment of type II diabetes, while for the other proteins, applications in the domains of oncology (FAP), immunology (DPP II) and the influencing of learning processes and memory (POP) have been proposed. For the rational design of inhibitor molecules, three main elements are used: enzymatic mechanism, substrate specificity, and 3D structure (modeling techniques). In the synthesis of inhibitors, combinatorial and parallel synthetic technologies are applied where feasible. Finally, the biochemical evaluation of compounds is carried out in close collaboration with experts in the field.

Researcher(s)

Research team(s)

Development of potent and selective inhibitors of fibroblast activation protein, a new target in the treatment of malignant diseases. 01/07/2007 - 31/12/2011

Abstract

The enzymatic activity of fibroblast activation protein (FAP) was recently shown to have a positive influence on tumor growth and mestastasis. This project is concerned with the systematic development of potent and selective inhibitors of FAP, with potential use in the further functional characterisation of the enzyme and the treatment of malignant diseases.

Researcher(s)

Research team(s)

Design, synthesis and evaluation of diverse enzyme inhibitors as potential antiparasitic compounds. 01/01/2007 - 31/12/2010

Abstract

The research application proposes a further extension of our efforts to develop potent and selective inhibitors for the target proteins, with a strong preference for enzymes involved in parasitic diseases as malaria and trypanosomiasis. In addition to the mere development of compounds with high activity and selectivity, we consider the development or the optimisation of synthetic methodologies for their preparation as an equally valid objective, as well as their funrther structural modification in order to obtain products with desirable pharmacokinetic profiles. A second objective is to investigate the selectivity of inhibitors that were reported by our and other groups with respect to related enzymes.

Researcher(s)

Research team(s)

Optimisation of urokinase inhibitors as potential anti-cancer agents. 01/01/2007 - 31/10/2007

Abstract

Urokinase inhibitors are important compounds in the development of new anti-cancer agents. This project aims at the de optimisation of diphenyl phosphonates, derived from basic amino acids as irreversible inhibitors of this enzym. The optimisation is focused on the synthesis of stable compounds with better biopharmaceutical properties.

Researcher(s)

  • Promotor: Haemers Achiel
  • Fellow: Abdel -Rahman Adel

Research team(s)

Synthesis and biological evaluation of nucleoside hydrolase inhibitors as trypanocidal compounds. 01/10/2006 - 30/09/2008

Abstract

Researcher(s)

Research team(s)

Identification of the in vivo binding partners of DPP IV inhibitors. 01/03/2006 - 31/12/2007

Abstract

Inhibitors of the proline selective dipeptidyl-peptidase IV (DPP IV) are currently under clinical trials for the treatment of type 2 diabetes. Using a proteome-wide scanning approach, we wish to map the in vivo binding partners of selected DPP IV inhibitors. Information obtained from this study can be relevant in selecting inhibitors for drug development or the preparation of new inhibitors with maximal DPP IV selectivity.

Researcher(s)

Research team(s)

Serine proteases in the development of new antiparasitic compounds. 01/01/2006 - 31/12/2007

Abstract

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Research team(s)

FWO Visiting Postdoctoral Fellowship. (Georgiana SURPATEANU) 01/10/2005 - 30/09/2006

Abstract

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Research team(s)

Peptide- and proteïn mimetics: a combinatorial approach via privileged templates. 01/02/2005 - 31/10/2009

Abstract

Researcher(s)

Research team(s)

Design, synthesis and avaluation of potent and selective inhibitors of prolyl peptidases of clan SC. 01/10/2004 - 30/09/2007

Abstract

Due to the unique structure of proline, relatively few peptidases are able to cleave peptide bonds containing proline. Many biologically active peptides contain an evolutionary conserved proline residue as a proteolytic-processing regulatory element, and therefore proline-specific peptidases are expected to be important 'check-point' controls with great potential as targets for drug discovery. Remarkably, in humans, all enzymes specific for cleaving of a Pro-Xaa bond, are found in clan SC. They share a serine nucleophile and a catalytic triad being in the linear order Ser-Asp-His. This project aims at the development of powerful and selective inhibitors for the catalytically active Pro-Xaa peptidases (DPP IV, DPP II, DPP 8, DPP 9, FAP and POP). Inhibitors will be used primarily for the full functional characterization of the different enzymes and, if possible, for their further validation as therapeutic targets. Inhibitors of DPP IV have been shown to be applicable in the treatment of type II diabetes, while for the other proteins, applications in the domains of oncology (FAP), immunology (DPP II) and the influencing of learning processes and memory (POP) have been proposed. For the rational design of inhibitor molecules, three main elements are used: enzymatic mechanism, substrate specificity, and 3D structure (modeling techniques). In the synthesis of inhibitors, combinatorial and parallel synthetic technologies are applied where feasible. Finally, the biochemical evaluation of compounds is carried out in close collaboration with experts in the field.

Researcher(s)

Research team(s)

Synthesis and biological evaluation of nucleoside hydrolase inhibitors as potential anti-parasitic agents. 01/10/2004 - 30/09/2006

Abstract

Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

Researcher(s)

  • Promotor: Augustyns Koen
  • Co-promotor: Haemers Achiel
  • Fellow: Goeminne Annelies

Research team(s)

Synthesis and biological evaluation of metalloproteinase and urokinase inhibitors as potential inhibitors of angiogenesis and metastasis. 01/10/2003 - 30/09/2005

Abstract

Angiogenesis is a fundamental process in reproduction and wound healing. Under these conditions, neovascularisation is tightly regulated. Unregulated angiogenesis is thought to be indispensable for solid tumor growth and metastasis. Hence, the inhibition of angiogenesis is considered to be one of the most promising strategies that might lead to the development of novel antineoplastic therapies. A plethora of angiogenic factors has been identified in the past 20 years. Most of them are not specific angiogenesis inducers. Urokinase-type plasminogen activator and a few members of the matrix metalloproteinase (MMP)family are considered as selective angiogenic factors and excellent targets for drug design. Urokinase is a serine protease. Compounds with diphenyl aminophosponate tripeptide structure are designed as possible inhibitors. These compounds are characterized by a guanidine or amidine as positioning group. A series of compounds will be synthesized and the guanidine-amidine containing aminophosphonic acid structure optimized. MMP's are zinc proteases and most inhibitors contain zinc binding groups such as hydroxamates. We will use the ?-ketophosphonic acid group as potential inhibiting group. The pseudopeptide structure will be derived from well known structures of the hydroxamate group of compounds, emphasizing the selectivity on MMP2 and MMP9, both involved in angiogenesis. Another series of MMP2 and MMP9 inhibitors to be synthesized are cyclopeptides in which different cyclic structures will be introduced.

Researcher(s)

Research team(s)

Design and synthesis of enzym inhibitors of serine proteases, cysteine proteases and C-N ligases with the aid of parallel solid phase synthesis. (FWO Vis.Fel., El-Tantawy El-Sayed Ibrahim) 01/07/2003 - 30/06/2004

Abstract

Prolyl oligopeptidase (POP) is an endopeptidase with serine protease activity that cleaves peptides after proline. Recently POP was isolated from infectious Trypanosoma cruzi, the causative agent of Chagas disease. The enzym plays a crucial role in the invasion of the parasites in mammalia cells, and is therefore a good target for the development of new drugs. POP inhibitors are indeed capable of preventing invasion. Furthermore, POP inhibitors developed in our laboratory are able to kill the parasite. In this project a whole series of POP inhibitors will be synthesised. The inhibitory potential of these inhibitors on the enzym will be investigated, as well as their antiparasitic properties in vitro and in vivo.

Researcher(s)

Research team(s)

N-ribohydrolases as activators of prodrugs. 01/03/2003 - 28/02/2007

Abstract

The objective is to design inactive non-toxic prodrugs that can be hydrolysed specifically into ribose and a toxic (parasiticidal) product by particular bacterial or parasitic N-ribohydrolases. The choice for bacterial and parasitic N-ribohdrolases, a family of enzymes that has no representatives within mammals as generic prodrug activating enzymes opens the way to two different prodrug strategies, leading to different therapeutic applications. The first prodrug strategy consists of killing particular bacteria or parasites by systemic cytotoxic compounds that are selectively activated by the parasite's N-ribohydrolase. By including the hyrolases of the genera Campylobacter, Escherichia, Staphylococcus, Trypanosoma, Plasmodium, Leishmania, Pseudomonas, Mycobacterium, and Toxoplasma, we aim to discover a number of new lead compounds that can be developed and validated for the treatment food poisoning and opportunistic infections and against (neglected) infectious diseases including malaria, tuberculosis, sleeping sickness, Chagas disease, and Leishmaniasis. Our second prodrug strategy is based on delivery techniques and includes the activation of non toxic compounds by exogenous ribohydrolases that are targeted to a particular cell type. In this part of the program, we would like to validate gated Self-Assembling NanoStructures (SONS) filled with ribohydrolases as nanoreactors to activate particular prodrugs `in situ'. To deliver these SONS to particular cells, specific single domain antibodies will be fused to theses nanoparticles by chemical or biochemical means.

Researcher(s)

Research team(s)

Design, synthesis and evaluation of inhibitors of nucleoside hydrolases and validation of these enzymes as targets in antiparasitic drug design. 01/01/2003 - 31/12/2006

Abstract

Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

Researcher(s)

Research team(s)

Design, synthesis and evaluation of inhibitors of nucleoside hydrolases and validation of these enzymes as target in anti-parasitic drug design. 01/01/2003 - 31/12/2006

Abstract

Nucleoside hydrolasen are important enzymes in the purine 'salvage pathway' of parasites such as plasmodia and trypanosoma. They are not found in mammalia. Inhibitors of these enzymes with iminoribitol and cyclopentenr structure are designed with molecular modelling and prepared. They are tested as inhibitors of nucleoside hydrolases and as antiparasitic agent.

Researcher(s)

Research team(s)

Non-peptide inhibitors of DPP IV and type II diabetes. 01/01/2003 - 31/12/2003

Abstract

Researcher(s)

  • Promotor: Haemers Achiel

Research team(s)

Synthesis and biological evaluation of nucleoside hydrolase inhibitors as potential anti-parasitic agents. 01/10/2002 - 30/09/2004

Abstract

Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

Researcher(s)

  • Promotor: Augustyns Koen
  • Co-promotor: Haemers Achiel
  • Fellow: Goeminne Annelies

Research team(s)

Design and development of antiangiogenic therapeutics : a multidisciplinary approach. 01/01/2002 - 31/12/2005

Abstract

Angiogenesis or the development of new bloodvessels from existing microvascular tissue is a fundamental aspect of many fysiological and pathological processes. Angiogenesis is of fundamental importance in the growth and metastasis of tumors and in chronic inflammatory diseases. Antiangiogenic therapeutics are therefore of potential use in cancer treatment and arthritis. The design and development of antiangiogenic therapeutics in this project will be done either on a rational way, either with at random control of chemical libraries. The rational approach will be based on the design of inhibitors of matrix metalloproteinases (MMP) or of urokinase type plasminogen activator (uPA). We will use ligand-based drug design based on the structure of known inhibitors and substrates and based on the enzymatic mechanism of the target. Since the 3D structure of the targets is known, we will also use structure-based drug desing. The at random approach will be based on the control of antiangiogenic activity of a library of chemical compounds isolated from nature. Especially certain saponins and dihydrobenzofuran lignans with promising acitvities will be further investigated

Researcher(s)

Research team(s)

Synthesis of a resin-bound absorptionmodel for a rapid in vitro evaluation of drug candidates. 01/01/2001 - 31/12/2003

Abstract

Recent developments in genomics, high-throughput screening and combinatorial chemistry enormously increased the amount of potential therapeutical targets and potential drugs. Because high-throughput determinations of the pharmacokinetic properties are not available, this may well become the rate-limiting step in drug discovery and development. Moreover, the existing pharmacokinetic research is labour- and time consuming and therefore very costly. During this project we will synthesise a drug absorption model on resins that should allow a high-throuhput screening of drug candidates for their absorption potential.

Researcher(s)

Research team(s)

Synthesis of phosphonylated amino acids and their oligopeptides for the design of new medicines and agrochemicals. 11/12/2000 - 11/12/2003

Abstract

Aminophosphonic and aminophosphinic acids and derived peptides or pseudopeptides are analogues of amino carboxylic acids and peptides. Several of these compounds have potential use as therapeutic or agrochemical agent. The following topics will be investigated : Total synthesis of antibiotic phosphonopeptides isolated from Bacillus subtilis and Streptomyces luridus. Synthesis of some analogues and evaluation of their biological properties. Synthesis of phosphonic and phosphinic derivatives of spermidine and incorporation in glutathion-like peptides as potential antileishmanial and antitrypanosomal agents. Synthesis of a library of aminophosphonic acids for use in therapeutic and agrochemical projects.

Researcher(s)

Research team(s)

Design and synthesis of enzyme inhibitors against serine proteases, cysteïne proteases en C-N ligases with parallel solid phase synthesis. 01/01/2000 - 31/12/2003

Abstract

Development of enzyme inhibitors is one of the most important topics in drug design and development. New structures will be designed using rational drug design methods and prepared in a parallel solid phase system. Targets are the trypanothione synthetase complex as potentiale trypanocide compounds; dipeptidylpeptidase IV and II inhibitors as potential drugs in immune related diseases and diabetes; prolylendopeptidases as potential drugs in brain disorders

Researcher(s)

Research team(s)