Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

• DOI: 10.1074/jbc.m117.806075
• Publication Date: 2017-09-01T00:40:23Z
• Authors: Robert H. Scannevin; Richard Alexander; Tara Mezzasalma H...; Sharon L. Burke; Monica Singer; Cuifen Huo; Yue-Mei Zhang; Diane Maguire; John Spurlino; Ingrid Deckman; Karen I. Carroll; Frank Lewandowski; Eric Devine; Keli Dzordzorme; Brett Tounge; Cindy Milligan; Shariff Bayoumy; Robyn Williams; Celine Schalk-Hihi; Kristi Leonard; Paul Jackson; Matthew Todd; Lawrence C. Kuo; Kenneth J. Rhodes
• Keywords: Zymogen; Matrix metalloproteinase inhibitor

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, particular, highly dynamically regulated several processes. Development MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, long history failed clinical trials demonstrated that broad-spectrum have limited utility, which spurred the development selective individual MMPs. Attaining selectivity technically challenging because sequence structural conservation across various Here, through biochemical screening paradigm, we identified JNJ0966, compound inhibited MMP-9 zymogen subsequent generation catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, or MMP-14 catalytic activity did not inhibit related MMP-2 zymogen. The molecular basis this was characterized interaction with pocket proximity to cleavage site near Arg-106, distinct from domain. efficacious reducing disease severity mouse experimental autoimmune encephalomyelitis model, demonstrating viability approach. This discovery reveals unprecedented pharmacological approach inhibition, providing opportunity improve future drug candidates. Targeting manner may also allow pharmaceutical exploration other enzymes previously viewed intractable targets.