2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 Jul 25;62(14):6482-6494. doi: 10.1021/acs.jmedchem.9b00575.
Pamela A Haile 1,  Linda N Casillas 1,  Bartholomew J Votta 1,  Gren Z Wang 1,  Adam K Charnley 1,  Xiaoyang Dong 1,  Michael J Bury 1,  Joseph J Romano 1,  John F Mehlmann 1,  Bryan W King 1,  Karl F Erhard 1,  Charles R Hanning 1,  David B Lipshutz 1,  Biva M Desai 1,  Carol A Capriotti 1,  Michelle C Schaeffer 1,  Scott B Berger 1,  Mukesh K Mahajan 1,  Michael A Reilly 1,  Rakesh Nagilla 1,  Elizabeth J Rivera 1,  Helen H Sun 1,  John K Kenna 1,  Allison M Beal 1,  Michael T Ouellette 1,  Mike Kelly 2,  Gillian Stemp 2,  Máire A Convery 2,  Anna Vossenkämper 3,  Thomas T MacDonald 3,  Peter J Gough 1,  John Bertin 1,  Robert W Marquis 1
Affiliations

Affiliations

  • 1 GlaxoSmithKline , Collegeville Road , Collegeville , Pennsylvania 19426 , United States.
  • 2 GlaxoSmithKline , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
  • 3 Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry , Queen Mary University of London , London E1 2AD , U.K.
PMID: 31265286 DOI: 10.1021/acs.jmedchem.9b00575
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.

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