6YJM

Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with the Inhibitor GLPG1972

6YJM の概要

• エントリーDOI: 10.2210/pdb6yjm/pdb
• 分子名称: A disintegrin and metalloproteinase with thrombospondin motifs 5, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: zinc metalloproteinase, aggrecanase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50586.08

構造登録者

Goepfert, A.,Leonard, P.,Triballeau, N.,Fleury, D.,Mollat, P.,Lamers, M. (登録日: 2020-04-03, 公開日: 2021-04-14, 最終更新日: 2024-01-24)

主引用文献

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

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: 33719441
DOI: 10.1021/acs.jmedchem.0c02008

実験手法

X-RAY DIFFRACTION (2.25 Å)