Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen

Doctoraten 2024

Public defence Siham Benramdane 13/02/2024 - Design and synthesis of selective DPP9 inhibitors- Department Pharmaceutical Sciences

Public defence Siham Benramdane 13/02/2024 - Design and synthesis of selective DPP9 inhibitors- Department Pharmaceutical Sciences

Promotors:

Prof. dr. Pieter Van der Veken
Prof. dr. Hans De Winter

Location: Aula R2, gebouw R, Campus Drie Eiken

Abstract:

The aim of this work is to design and synthesize selective inhibitors targeting dipeptidyl peptidase 9 (DPP9), a challenging goal considering the high sequence similarity between DPP9 and other related enzymes, such as DPP4 but especially DPP8. DPP9 has been gaining interest recently as a pivotal role in inflammatory cell death (pyroptosis) could be attributed to DPP9, which lead to the identification of DPP9 as a therapeutic target in acute myeloid leukemia (AML).

The thesis primarily concentrates on crafting dipeptide-derived DPP9 inhibitors, inspired by the N-terminal dipeptides of known substrates. By using the marketed DPP4 inhibitor Vildagliptin as a reference, the design strategy involves a bimodular structure incorporating a proline-mimetic as the P1 unit, with or without a nitrile electrophilic warhead, while allowing certain flexibility in the P2 fragment. Vildagliptin's N-(3-hydroxyadamantyl)glycine moiety was thoroughily investigated, by replacing the alcohol group with a variety of functional groups. As a result, several promising compounds have been obtained, exhibiting promising potency and selectivity for DPP9. Notably, compounds 42 and 47 emerged as top candidates, exhibiting low nanomolar DPP9 affinity (3 – 4 nM) alongside significant DPP9-to-DPP8 selectivity indices, in the magnitude of two orders.

This comprehensive study not only presents a strategic evolution in designing DPP9-selective inhibitors, but also sheds light on the structural nuances influencing selectivity, providing valuable insights for future drug development and understanding enzyme differentiation in this class.

Public defence Karuna Adhikari 30/01/2024 - Design, synthesis, and evaluation of trans-cyclooctene (TCO) and cis- dioxolane fused TCO (d-TCO) probes for bioorthogonal pretargeted PET imaging - Department Pharmaceutical Sciences

Public defence Karuna Adhikari 30/01/2024 - Design, synthesis, and evaluation of trans-cyclooctene (TCO) and cis- dioxolane fused TCO (d-TCO) probes for bioorthogonal pretargeted PET imaging - Department Pharmaceutical Sciences

Promotors:

Prof. dr. Koen Augustyns
Prof. dr. Sigrid Stroobants
Prof. dr. Filipe Elvas

Location: Aula O.05, gebouw O, Campus Drie Eiken

Abstract:

Immuno-positron emission tomography (PET) imaging using radiolabeled monoclonal antibodies (mAbs) is a powerful tool with high specificity and sensitivity for cancer diagnosis and therapy response monitoring. However, slow mAb pharmacokinetics require the use of long-lived radioisotopes, resulting in suboptimal target-to-background ratios and high radiation exposure in patients. To address this, a pretargeting strategy based on the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine was proposed. In this approach, an mAb-conjugated bioorthogonal tag is initially administered, allowing clearance from circulation. Subsequently, a radiolabeled reaction partner is injected, which covalently binds to the tag on the mAb. This allows the use of short-lived radioisotopes such as Fluorine-18, consequently minimizing radiation exposure while enhancing in vivo imaging contrast. The TCO-tetrazine ligation is a perfect candidate and has been extensively studied for this application. In this project, we focused on the development and characterization of fluorinated TCO and cis-dioxolane-fused TCO (d-TCO) derivatives as radiolabeled reaction partners with CC49 (anti-TAG-72) mAb-conjugated tetrazine tags for in vivo pretargeted imaging in mice bearing LS174T colorectal tumor xenografts. Based on previous studies, a novel [18F]FTCO derivative with a chelator linker was developed and evaluated in a mouse model of colorectal cancer xenografts. The 18F-labeled TCO derivative showed improved in vivo stability and demonstrated clear visualization of tumor tissue in the pretargeted group when compared to the control. Furthermore, a small library of d-TCO derivatives with enhanced reaction kinetics and diverse linkers was developed. Two of these compounds demonstrated excellent in vivo ligation in a pre-targeted blocking assay. Further radiochemical development and analysis revealed higher in vivo stability and favorable clearance of the 18F-labeled d-TCO derivative containing a squaramide linker. This radiotracer also showed a significant difference in tumor uptake compared with the control group in pretargeted imaging. Additionally, d-TCO derivatives were tested in a turn-on fluorescence-based cell permeability assay to visualize internalizing or intracellular targets. A d-TCO derivative containing a cyclobutyl fluoride linker exhibited excellent intracellular ligation in this assay. Although further fine-tuning of the linkers is required to obtain improved image contrast, this project demonstrates the potential of TCO- and d-TCO-based radiotracers in pretargeted PET imaging and provides insights for future probe development.