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Discovery of a first-in-class Receptor Interacting Protein 2 (RIP2) kinase specific clinical candidate, 2-((4-(Benzo[ d ]thiazol-5-ylamino)-6-( tert -butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases

DOI: 10.1021/acs.jmedchem.9b00575 DOI Help

Authors: Pamela A. Haile (GlaxoSmithKline) , Linda N. Casillas (GlaxoSmithKline) , Bartholomew J. Votta (GlaxoSmithKline) , Gren Z. Wang (GlaxoSmithKline) , Adam K. Charnley (GlaxoSmithKline) , Xiaoyang Dong (GlaxoSmithKline) , Michael J. Bury (GlaxoSmithKline) , Joseph J. Romano (GlaxoSmithKline) , John F. Mehlmann (GlaxoSmithKline) , Bryan W. King (GlaxoSmithKline) , Karl F. Erhard (GlaxoSmithKline) , Charles R. Hanning (GlaxoSmithKline) , David B. Lipshutz (GlaxoSmithKline) , Biva M. Desai (GlaxoSmithKline) , Carol A. Capriotti (GlaxoSmithKline) , Michelle C. Schaeffer (GlaxoSmithKline) , Scott B. Berger (GlaxoSmithKline) , Mukesh K. Mahajan (GlaxoSmithKline) , Michael A. Reilly (GlaxoSmithKline) , Rakesh Nagilla (GlaxoSmithKline) , Elizabeth J. Rivera (GlaxoSmithKline) , Helen H. Sun (GlaxoSmithKline) , John K. Kenna (GlaxoSmithKline) , Allison M. Beal (GlaxoSmithKline) , Michael T. Ouellette (GlaxoSmithKline) , Mike Kelly (GlaxoSmithKline) , Gillian Stemp (GlaxoSmithKline) , Máire A. Convery (GlaxoSmithKline) , Anna Vossenkämper (GlaxoSmithKline) , Thomas T. Macdonald (Queen Mary University of London) , Peter J. Gough (GlaxoSmithKline) , John Bertin (GlaxoSmithKline) , Robert W. Marquis (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 1195 , 5799

Abstract: RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Subject Areas: Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography