Research team

Medicinal Chemistry (UAMC)

Expertise

Medicinal chemistry & drug discovery, pharmaceutical chemistry, organic chemistry & organic synthesis

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)

Treatment of autophagy deficits in Charcot-Marie-Tooth disease caused by mutations in the small heat shock proteins HSPB1 and HSPB8. 01/01/2021 - 31/12/2024

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, including Charcot-Marie-Tooth (CMT) neuropathy. In this framework, basic research and drug development have a strong need for reliable, drug-like autophagy inducers. We carried out a phenotypic high-throughput screen on compounds that were preselected based on drug likeness parameters. In total, 3 distinct chemical families were identified that previously have not been associated with autophagy induction. After thorough validation, potency and gross mode-of-action studies, the most promising chemical family was prioritized. Structure-activity relationships will be constructed for this chemical family. In addition, chemical optimization will be pursued to obtain novel representatives with further improved potency and a maximally favorable physicochemical profile. Efforts will be done for target finding. All novel compounds will be thoroughly investigated in a cell model for CMT neuropathy associated with mutations in the small heat shock proteins HSPB1 and HSPB8. To fully characterize this translational potential, in vivo evaluation in an established mouse model will be carried out for one maximally optimized compound.

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Research team(s)

The role of dipeptidyl peptidase 9 (DPP9) in human monocyte-derived macrophages: Discovery of DPP9 binding partners & natural substrates using novel chemical and cellular tools. 01/01/2021 - 31/12/2024

Abstract

Preliminary evidence shows that the enzyme dipeptidyl peptidase 9 (DPP9), which is present in macrophages, plays a role in controlling the inflammatory response and associated cell death. Inflammation is a normal response of tissues against infections, chemical insults and physical injuries. However, in some cases, it becomes chronic and causes harm. A better understanding of the inflammatory process provides new therapeutic opportunities. In this project, we will focus on the role of the intracellular protease DPP9 in macrophages derived from human white blood cells. The crystal structure of DPP9 was recently solved, and can now be used to design DPP9 inhibitors. We will develop selective and potent DPP9 inhibitors and substrates. We will also engineer the human THP-1 cell line to eliminate DPP9. Using the DPP9 inhibitors and engineered cell lines, we will determine under which conditions DPP9 plays a key role in macrophage function. Finally, the molecular binding partners of DPP9 will be identified. We will look for natural substrates as well as non-substrate interaction partners of DPP9 in macrophages. The interactions will be characterized at the molecular level. Our fundamental biochemical findings and novel chemical tools will significantly advance the development of future therapies for diseases where DPP9 plays a role.

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Research team(s)

Autophagy in inflammation and inflammatory disorders (ATLANTIS), from basicinsights to experimental therapy. 01/01/2021 - 31/12/2024

Abstract

Autophagy is crucial in the (patho)physiology, including inflammation, infection and cancer.Autophagy functions as a survival mechanism by maintaining viability during periods of stress, and byremoving damaged organelles and toxic metabolites, such as protein aggregates or intracellular pathogens. The Atlantis research consortium (AuTophagy in InfLAmmatioN and inflammaTory dISorders) brings together a team of expert investigators from the complementary fields of autophagy, (cancer) cell death signaling, inflammation signaling, angiogenesis and atherosclerosis, and drug screening and medicinal chemistry. We will study in an integrated way the impact of autophagy and its pharmacological modulation in various vascular diseases with a focus on the endothelium and its functional interaction with immune cells in sepsis, tumor-driven (lymph)angiogenesis, and atherosclerosis.

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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.

Researcher(s)

Research team(s)

Cell death detection platform. 01/01/2020 - 31/12/2021

Abstract

We request funding for two basic infrastructure equipment to measure cell death along any other biochemical parameter that is crucial to determine the mode of cell death such as caspase activation, reactive oxygen species, calcium, mitochondrial membrane potential, lysosomal leakage and lipid peroxidation: 1) FLUOstar® Omega plate reader with atmospheric control unit and 2) BD Accuri C6 Plus personal flow cytometer. These two instruments are perfectly complementary, while the Fluostar provides average values measured on cell populations seeded in any plate up to 384-well plates, the Accuri analyzes at the single cell level allowing to detect heterogenous responses. If the transition from Pathophysiology lab (headed by Patrick D'Haese until 2020) to Cell Death and Inflammation research lab (headed by Tom Vanden Berghe from 2020 onwards) is to proceed smoothly, the investment in this basic but crucial equipment to analyze cell death and related biochemical features is highly needed. Investment in the cell death platform at UAntwerp will boost the recently initiated collaborations in the field of cell death research at UAntwerp. Cell death research is highly present but scattered within the Faculties of FBD and GGW, therefore we initiated monthly sessions of the Cell Death Hot Talks (supported by the OEC Infla-Med). These sessions will (i) increase the exchange on ongoing cell death research, (ii) lead to sharing tools and (iii) boost potential collaborations. Along this line of sharing cell death related expertise and tools, there is a high need to setup a platform to measure and type the mode of cell death within the faculties of FBD and GGW. This investment fits well in the long-term strategic plan in which cell death is one of the four research clusters within the Department of Biomedical Sciences. Moreover, the cell death platform could be instrumental as a steppingstone to make cell death an Emerging Frontline Research Domain.

Researcher(s)

Research team(s)

Pharmacological modulation of autophagy in vascular disease. 01/12/2019 - 30/11/2023

Abstract

Despite recent scientific and technological advances, vascular disease remains the leading cause of morbidity and mortality in Europe. Autophagy, a subcellular process for bulk destruction of proteins and organelles in lysosomes, is an essential in vivo process mediating proper vascular function. Because impaired or defective autophagy underlies major phenotypic signatures of vascular disease, there is an urgent need for pharmacological interventions with compounds that stimulate autophagy in the vasculature. In order to fulfill this need, a PhD student (affiliated to the Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences) will be recruited to constitute a reliable platform for hit-to-lead optimization of autophagy-inducing drugs and to characterize their mode of action. Moreover, a postdoctoral researcher (affiliated to the Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences) will be hired to initiate the evaluation of autophagy induction in mouse models of vascular disease such as arterial stiffening and atherosclerosis.

Researcher(s)

Research team(s)

Development of tools and methods for the evaluation of FAP as a predictive/prognostic biomarker in cancer. 01/11/2019 - 31/10/2023

Abstract

Immunotherapy shows great potential in the treatment of cancer. Unfortunately, primary resistance is frequently occurring, hence the urgent need for biomarkers. Fibroblast activation protein (FAP), an enzyme that is selectively expressed in cancer-associated fibroblasts in 90% of all human epithelial tumors, may become a promising predictive biomarker for immunotherapy resistance. However, to date, there are no validated, specific tools to determine FAP expression and/or activity within the tumor microenvironment (TME). Therefore, the first goal of this project, is the development of specific tools and accurate methods to detect FAP within the TME. We will develop 2 fluorescent FAP-assays, one based on a fluorescently labelled inhibitor and the other on a fluorescently labelled anti-FAP antibody. The third assay is based on a FAP-specific substrate for histochemistry that allows in situ amplification of the signal. Secondly, early detection of metastasis remains a major hurdle in diagnosis and there is an urgent need to explore new biomarkers of early metastasis. Recently, it is suggested that circulating FAP +cCAFs within the blood of metastatic patients could be interesting for that purpose. Nonetheless, no specific, accurate tools and techniques are available for identification and enrichment of FAP +cCAFs. Consequently, the second goal of this project is to develop new tools and methods to identify and enrich FAP+cCAFs in the peripheral blood of metastatic cancer patients

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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)

Personalized immune therapy: FAP as a marker for resistance to immune checkpoint therapy in urothelial carcinomas. 01/09/2019 - 31/12/2021

Abstract

(This research project aims to acquire dedicated knowledge on the protein 'Fibroblast activation protein alpha', further called 'FAP', in the context of personalized immune therapy. We will investigate whether FAP can be a biomarker for resistance to immunotherapy in urothelial carcinomas. In addition, we explore the presence of FAP in urine (as a non-invasive biological biomatrix) to monitor or predict the response to therapy for urothelial carcinomas.

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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.

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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.

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Research team(s)

Development of novel cell death PET imaging probes for early treatment response assessment. 01/10/2018 - 30/09/2022

Abstract

Apoptosis or programmed cell death plays a major role not only in the pathogenesis but also in the treatment of cancer. In recent years, a variety of novel cell death inducing molecular cancer therapies have entered the clinic. Although many demonstrated their potential as effective treatment options in several types of cancer, costs to patients and the healthcare system are often staggering. Moreover, most anti-cancer treatments are linked to toxicity to healthy tissues. Early objective and accurate evaluation of tumor response to therapy is therefore of great importance. Tumor response assessment based upon the molecular effects of therapies, such as cell death induction, is a promising strategy for early prediction of therapy outcome. The availability of a radiotracer for positron emission tomography (PET) imaging of cell death could offer clinicians a tool to early after onset of treatment predict individualized responses in patients, and aid in personalized and cost-reducing patient care. Activation of caspase-3 and exposure of phosphatidylethanolamine (PE) represent key biomarkers for apoptosis. Currently no caspase-3 selective nor PE targeting PET radiotracers are available. This project therefore aims at developing novel caspase-3 selective and PE targeting radiotracers for PET imaging of cell death. Both cell death targeting strategies will be compared for early in vivo evaluation of response to therapy (immunotherapy and multi-kinase inhibitor treatment in preclinical models of colorectal cancer).

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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 - 31/03/2022

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)

Biopharmaceutical optimization of PET-diagnostic tools targeting fibroblast activation protein (FAP). 01/05/2020 - 30/09/2021

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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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)

The Biomolecular Interaction Platform (BIP) at UAntwerp. 01/05/2018 - 30/04/2021

Abstract

Physical and functional interactions between biomolecules play pivotal roles in all aspects of human health and disease. Gaining a greater understanding of these biomolecular interactions will further expand our understanding of diseases such as cancer, metabolic diseases and neurodegeneration. At UAntwerp, 7 research groups have joined forces to obtain the absolutely necessary equipment to measure these interactions with a Biomolecular Interactions Platform (BIP). This will allow to detect interactions and precisely determine binding affinities between any kind of molecule, from ions and small molecules to high-molecular weight and multi-protein complexes. The BIP will also allow to identify collateral off- targets, crucial in the drug discovery field. Access to a BIP will strongly support ongoing research projects and bring research within the BIP-consortium to a higher level. Since biomolecular interactions are highly influenced by the methodology, it is recommended to measure the interaction by several, independent techniques and continue with the most appropriate one. For this reason, the consortium aims at installing a BIP, consisting of several complementary instruments that each measure biomolecular interactions based on different physical principles. They wish to expand the existing Isothermal Titration Calorimetry with two complementary state-of-the- art techniques: MicroScale Thermophoresis and Grating- Coupled waveguide Interferometry.

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Research team(s)

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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Research team(s)

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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Research team(s)

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.

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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.

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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.

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"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.

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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.

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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.

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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.

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Prolyl oligopeptidase: partners and pathways in neuronal function and neurodegeneration. 01/01/2015 - 31/12/2018

Abstract

In this project we aim (1) to characterize at the molecular level the role of PREP in hallmark processes of neurodegenerative disease: neuronal death, synapse loss and neuroinflammation; and (2) to investigate whether PREP-inhibitors can be used to modulate these processes.

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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.

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Partial placement of the NMR infrastructure for the structural elucidation of synthetic and natural substances. 19/05/2014 - 31/12/2018

Abstract

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

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Creation of a preclinical platform at the UA for testing novel therapeutic approaches against ocular surface diseases. 01/01/2014 - 31/12/2015

Abstract

Ocular Surface diseases (OSD) such as dry eye syndrome (DES) show an estimated prevalence between 15 and 29%. The only FDA approved and on subscription dry-eye treatment is cyclosporine 0.05% (Restasis®), but this formulation is not available in the EU. Novel therapies for OSD are therefore needed. The expertise within ADDN fosters a unique opportunity to set up a preclinical platform on OSD leading to an increased collaboration with industrial partners.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Secondary organic aerosol formation from monoterpenes: gaps in our current understanding. 01/01/2011 - 31/12/2014

Abstract

The major objectives of the project are to unravel the role of terpenylic acid and related compounds. We hypothesize that these compounds are key monomers of the clusters formed in the early stages of new particle formation, as well as of polar and higher-molecular weight (MW) products formed upon chemical aging, owing to the reactivity of the lactone group.

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    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.

    Researcher(s)

    Research team(s)

    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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    Research team(s)

    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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    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.

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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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    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.

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    Bacterial virulence as new target for protease inhibitors. 01/01/2009 - 31/12/2012

    Abstract

    The goal of this project is to gain insight in the role and applicability of protease (DPP4) inhibitors in bacterial infections. The proof-of-concept will be obtained in Porphyromonas gingivalis models with the following objectives and work packages: 1. Development of in vitro and in vivo virulence models for P. gingivalis. 2. Evaluation of enzyme inhibitors using purified recombinant P. gingivalis DPP4. 3. Evaluation of DPP/protease inhibitors in bacterial in vitro and in vivo models. 4. SAR and optimisation of the lead compounds. 5. Biochemical characterisation of lead compound-target enzyme interactions.

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    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.

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    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.

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    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.

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    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)

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    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.

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    Research team(s)

    Synthesis and biological evanluation of fluoroalkene- andphosphonamide analogues of proline as potential inhibitors of dipeptidyl peptidase IV. 01/10/2001 - 30/09/2003

    Abstract

    Dipeptidylpeptidase IV is an important target enzyme in the development of new drugs with antidiabetic and immunomodulating activity. Prolinephosfonates were developed as irreversible inhibitors of this enzym. These compounds were shown to be very active in "in vivo" testssystems. In this project the prolinephosphonate structure will be optimised by introducing fluoroalkene- and phosphinamide moieties.

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      Synthesis and biological evanluation of fluoroalkene- andphosphonamide analogues of proline as potential inhibitors of dipeptidyl peptidase IV. 01/10/1999 - 30/09/2001

      Abstract

      Dipeptidylpeptidase IV is an important target enzyme in the development of new drugs with antidiabetic and immunomodulating activity. Prolinephosfonates were developed as irreversible inhibitors of this enzym. These compounds were shown to be very active in "in vivo" testssystems. In this project the prolinephosphonate structure will be optimised by introducing fluoroalkene- and phosphinamide moieties.

      Researcher(s)

      Research team(s)