Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.; Choi, Jun Yong; Hart, P. John; Roush, William R.; Fields, Gregg B.; Hodder, Peter S.; Minond, Dmitriy

doi:10.1021/jm501284e

Title: Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

Journal Article · Mon Oct 20 00:00:00 UTC 2014 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/jm501284e · OSTI ID:1164950

Spicer, Timothy P. ^[1]; Jiang, Jianwen ^[2]; Taylor, Alexander B. ^[2]; Choi, Jun Yong ^[3]; Hart, P. John ^[4]; Roush, William R. ^[3]; Fields, Gregg B. ^[5]; Hodder, Peter S. ^[6]; Minond, Dmitriy ^[7]

Scripps Research Inst., Jupiter, FL (United States). Lead Identification Division
Univ. of Texas, San Antonio, TX (United States). Health Science Center, Dept. of Biochemistry and X-ray Crystallography, Core Lab.
Scripps Research Inst., Jupiter, FL (United States). Dept. of Chemistry
Univ. of Texas, San Antonio, TX (United States). Health Science Center, Dept. of Biochemistry and X-ray Crystallography, Core Lab.; South Texas Veterans Health Care System, San Antonio, TX (United States). Dept. of Veterans Affairs
Torrey Pines Inst. for Molecular Studies, Port St. Lucie, FL (United States). Dept. of Chemistry and Biology
Scripps Research Inst., Jupiter, FL (United States). Lead Identification Division; Scripps Research Inst., Jupiter, FL (United States). Dept. of Molecular Therapeutics
Scripps Research Inst., Jupiter, FL (United States). Lead Identification Division; Torrey Pines Inst. for Molecular Studies, Port St. Lucie, FL (United States). Dept. of Chemistry and Biology

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$$-$$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S₁' subsite and in an S₁/S₂* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$$-$$drug interactions in humans.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1164950

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 57; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14 Blagg, Julian A.; Noe, Mark C.; Wolf-Gouveia, Lilli A. Bioorganic & Medicinal Chemistry Letters, Vol. 15, Issue 7 https://doi.org/10.1016/j.bmcl.2005.02.038	journal	April 2005
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Analysis of the combined effect of two linear inhibitors on a single enzyme Martinez-Irujo, Juan J.; Villahermosa, María L.; Mercapide, Javier Biochemical Journal, Vol. 329, Issue 3 https://doi.org/10.1042/bj3290689	journal	February 1998
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Biochemical Characterization of Human Collagenase-3 Knäuper, Vera; López-Otin, Carlos; Smith, Bryan Journal of Biological Chemistry, Vol. 271, Issue 3 https://doi.org/10.1074/jbc.271.3.1544	journal	January 1996
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Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage Pratta, Michael A.; Yao, Wenqing; Decicco, Carl Journal of Biological Chemistry, Vol. 278, Issue 46 https://doi.org/10.1074/jbc.M303737200	journal	November 2003
The Roles of Substrate Thermal Stability and P2 and P1′ Subsite Identity on Matrix Metalloproteinase Triple-helical Peptidase Activity and Collagen Specificity Minond, Dmitriy; Lauer-Fields, Janelle L.; Cudic, Mare Journal of Biological Chemistry, Vol. 281, Issue 50 https://doi.org/10.1074/jbc.M606004200	journal	December 2006
Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects Johnson, Adam R.; Pavlovsky, Alexander G.; Ortwine, Daniel F. Journal of Biological Chemistry, Vol. 282, Issue 38 https://doi.org/10.1074/jbc.M703286200	journal	September 2007
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The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma Fields, Gregg B. Cells, Vol. 8, Issue 9 https://doi.org/10.3390/cells8090984	journal	August 2019
Design and Structural Evolution of Matrix Metalloproteinase Inhibitors Fischer, Thomas; Senn, Nicole; Riedl, Rainer Chemistry – A European Journal, Vol. 25, Issue 34 https://doi.org/10.1002/chem.201805361	journal	May 2019
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Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies Amar, Sabrina; Fields, Gregg B. Expert Review of Proteomics, Vol. 12, Issue 5 https://doi.org/10.1586/14789450.2015.1069190	journal	July 2015
Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate Madoux, Franck; Dreymueller, Daniela; Pettiloud, Jean-Phillipe RWTH Aachen University https://doi.org/10.18154/rwth-conv-212438	text	January 2016
The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma Fields, Gregg B. Cells, Vol. 8, Issue 9 https://doi.org/10.3390/cells8090984	journal	August 2019

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