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

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.
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [3] ;  [5] ;  [6] ;  [7]
  1. Scripps Research Inst., Jupiter, FL (United States). Lead Identification Division
  2. Univ. of Texas, San Antonio, TX (United States). Health Science Center, Dept. of Biochemistry and X-ray Crystallography, Core Lab.
  3. Scripps Research Inst., Jupiter, FL (United States). Dept. of Chemistry
  4. 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
  5. Torrey Pines Inst. for Molecular Studies, Port St. Lucie, FL (United States). Dept. of Chemistry and Biology
  6. Scripps Research Inst., Jupiter, FL (United States). Lead Identification Division; Scripps Research Inst., Jupiter, FL (United States). Dept. of Molecular Therapeutics
  7. 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
Publication Date:
OSTI Identifier:
1164950
Grant/Contract Number:
W-31-109-ENG-38; NCI P30CA054174; MH078948-01; U54MH074404; CA098799; AR063795
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 57; Journal Issue: 22; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES