Inflammatory caspases

Current work on the inflammatory caspases (mainly caspase-1) was initiated as an application of the MSAS approach discussed below. This fragment-based methodology identified several carboxylate isostere-containing building blocks suitable for construction of caspase inhibitors. Structurally novel small molecules targeting caspase 1 have meanwhile been prepared with these fragments. Ongoing work is evaluating the application of the fragments in “on-target” caspase inhibitor synthesis.


In 2015, a project was initiated aimed at the discovery of small molecule compounds to inhibit the protein-protein interaction of the pro-inflammatory cytokine TSLP with its receptor (TSLPR). Computational design, molecular dynamics and wet lab synthesis are integrated and initial results are in press in Nature Communications.17


17. Verstraete, K.; Peelman, F.; Braun, H.; Van Rompaey, D.; Dansercoer, A.; Vandenberghe, I.; Pauwels, K.; Tavernier, J.; De Winter, H.; Beyaert, R.; Lippens, G.; Lopez, J.; Lambrecht, B.; Hammad, H.; Savvides, S. Structure and antagonism of the receptor compex mediated by human TSLP in allergy and asthma. Nature Communications 2017, 8, 14937.

Trypsin-like proteases in inflammation

Over the years, UAMC developed a library of covalent inhibitors of trypsin-like proteases of about 250 members. Initially, compounds were targeted against urokinase plasminogen activator (uPA),18-20 but gradually this library was profiled against a panel of 20 serine proteases. This resulted in the identification of a compound that showed promising anti-inflammatory properties in a dry eye rat disease model.21 Also, interesting properties were demonstrated in a rat inflammatory bowel disease and a rat irritable bowel syndrome (IBD/IBS) model.22 This series of compounds are investigated for drug-like properties, patent protected and are ready to be out-licensed to a spin-off company.


18. Joossens, J.; Van der Veken, P.; Lambeir, A. M.; Augustyns, K.; Haemers, A. Development of irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator. J. Med. Chem. 2004, 47, 2411-2413.19. Joossens, J.; Van der Veken, P.; Surpateanu, G.; Lambeir, A. M.; El-Sayed, I.; Ali, O. M.; Augustyns, K.; Haemers, A. Diphenyl phosphonate inhibitors for the urokinase-type plasminogen activator: Optimization of the P4 position. J. Med. Chem. 2006, 49, 5785-5793.20. Joossens, J.; Ali, O. M.; El-Sayed, I.; Surpateanu, G.; Van der Veken, P.; Lambeir, A. M.; Setyono-Han, B.; Foekens, J. A.; Schneider, A.; Schmalix, W.; Haemers, A.; Augustyns, K. Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties. J. Med. Chem. 2007, 50, 6638-6646.21. Fissers, J.; Waldron, A. M.; De Vijlder, T.; Van Broeck, B.; Pemberton, D. J.; Mercken, M.; Van der Veken, P.; Joossens, J.; Augustyns, K.; Dedeurwaerdere, S.; Stroobants, S.; Staelens, S.; wyffels, L. Synthesis and Evaluation of a Zr-89-Labeled Monoclonal Antibody for Immuno-PET Imaging of Amyloid-beta Deposition in the Brain. Mol. Imaging. Biol. 2016, 18, 598-605.22.Ceuleers, H.; Van Spaendonk, H.; Hanning, N.; Heirbaut, J.; Lambeir, A. M.; Joossens, J.; Augustyns, K.; De Man, J. G.; De Meester, I.; De Winter, B. Y. Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases. World J. Gastroenterol. 2016, 22, 10275-10286.

Selective glucocorticoid receptor agonists (SEGRA's)​

In a small project, covalently binding SEGRA’s were developed.23


23. Ryabtsova, O.; Joossens, J.; Van der Veken, P.; Berghe, W. V.; Augustyns, K.; De Winter, H. Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition. Bioorg. Med. Chem. Lett. 2016, 26, 5032-5038.