3ELM

Crystal Structure of MMP-13 Complexed with Inhibitor 24f

Summary for 3ELM

• Entry DOI: 10.2210/pdb3elm/pdb
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: metallo-enzyme, mmp-13, carboxylate inhibitor, calcium, collagen degradation, disease mutation, extracellular matrix, glycoprotein, hydrolase, metal-binding, metalloprotease, polymorphism, protease, secreted, zinc, zymogen
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P45452
• Total number of polymer chains: 2
• Total formula weight: 40034.20

Authors

Kulathila, R.,Monovich, L.,Koehn, J. (deposition date: 2008-09-22, release date: 2009-07-21, Last modification date: 2024-02-21)

Primary citation

Monovich, L.G.,Tommasi, R.A.,Fujimoto, R.A.,Blancuzzi, V.,Clark, K.,Cornell, W.D.,Doti, R.,Doughty, J.,Fang, J.,Farley, D.,Fitt, J.,Ganu, V.,Goldberg, R.,Goldstein, R.,Lavoie, S.,Kulathila, R.,Macchia, W.,Parker, D.T.,Melton, R.,O'Byrne, E.,Pastor, G.,Pellas, T.,Quadros, E.,Reel, N.,Roland, D.M.,Sakane, Y.,Singh, H.,Skiles, J.,Somers, J.,Toscano, K.,Wigg, A.,Zhou, S.,Zhu, L.,Shieh, W.C.,Xue, S.,McQuire, L.W.
Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13
J.Med.Chem., 52:3523-3538, 2009

PubMed Abstract: The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).

PubMed: 19422229
DOI: 10.1021/jm801394m

Experimental method

X-RAY DIFFRACTION (1.9 Å)