6YJM
Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with the Inhibitor GLPG1972
Summary for 6YJM
| Entry DOI | 10.2210/pdb6yjm/pdb |
| Descriptor | A disintegrin and metalloproteinase with thrombospondin motifs 5, ZINC ION, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | zinc metalloproteinase, aggrecanase, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 50586.08 |
| Authors | Goepfert, A.,Leonard, P.,Triballeau, N.,Fleury, D.,Mollat, P.,Lamers, M. (deposition date: 2020-04-03, release date: 2021-04-14, Last modification date: 2024-01-24) |
| Primary citation | Brebion, F.,Gosmini, R.,Deprez, P.,Varin, M.,Peixoto, C.,Alvey, L.,Jary, H.,Bienvenu, N.,Triballeau, N.,Blanque, R.,Cottereaux, C.,Christophe, T.,Vandervoort, N.,Mollat, P.,Touitou, R.,Leonard, P.,De Ceuninck, F.,Botez, I.,Monjardet, A.,van der Aar, E.,Amantini, D. Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. J.Med.Chem., 64:2937-2952, 2021 Cited by PubMed Abstract: There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochemical activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC < 1.5 μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618). PubMed: 33719441DOI: 10.1021/acs.jmedchem.0c02008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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