Crystal structure of the pro form of a matrix metalloproteinase and an allosteric processing inhibitor

US8753857B2 · kind B2 · utility

Assignee

• Janssen Pharmaceutica NA · BE

Inventors

• Kristi A. Leonard · West Chester, US
• Richard S. Alexander · Newark, US
• Joseph Kent Barbay · Flourtown, US
• Roger F. Bone · Bound Brook, US
• Ingrid Deckman · Berwyn, US
• Paul F. Jackson · Bel Air, US
• Lawrence C. Kuo · Solebury, US
• Frank A. Lewandowski · Philadelphia, US
• Diane M. Maguire · Downingtown, US
• Cynthia M. Milligan · Rutledge, US
• Kenneth Rhodes · Belmont, US
• Robert Scannevin · Hopkinton, US
• Celine Schalk-Hihi · Phoenixville, US
• Barry A. Springer · Wilmington, US
• John Spurlino · Linglestown, US
• Matthew Todd · Spring House, US
• Brett A. Tounge · Blue Bell, US
• Aihua Wang · Jamison, US

Key dates

• Filing date: Jun 26, 2012
• Grant date: Jun 17, 2014
• Expiry date: Jun 26, 2032

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12Y304/24035
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.