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Published online before print November 27, 2007, 10.1110/ps.073130208
Protein Science (2008), 17:66-71. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Characterization of an exosite binding inhibitor of matrix metalloproteinase 13

Lata T. Gooljarsingh1, Ami Lakdawala2, Frank Coppo2, Lusong Luo1, Gregg B. Fields3, Peter J. Tummino1, and Richard R. Gontarek1

1 Oncology CEDD, Department of Enzymology and Mechanistic Pharmacology, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA
2 Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA
3 Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, USA

(RECEIVED July 19, 2007; FINAL REVISION September 24, 2007; ACCEPTED September 27, 2007)

Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors.

Keywords: matrix metalloproteinase 13; pyrimidine dicarboxamides; hydroxamates; synergism; mutual exclusivity; inhibition


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