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. 2017 Feb 23;60(4):1247-1261.
doi: 10.1021/acs.jmedchem.6b01751. Epub 2017 Feb 10.

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases

Philip A Harris, Scott B Berger, Jae U Jeong, Rakesh Nagilla, Deepak Bandyopadhyay, Nino Campobasso, Carol A Capriotti, Julie A Cox, Lauren Dare, Xiaoyang Dong, Patrick M Eidam, Joshua N Finger, Sandra J Hoffman, James Kang, Viera Kasparcova, Bryan W King, Ruth Lehr, Yunfeng Lan, Lara K Leister, John D Lich, Thomas T MacDonald  1 , Nathan A Miller, Michael T Ouellette, Christina S Pao, Attiq Rahman, Michael A Reilly, Alan R Rendina, Elizabeth J Rivera, Michelle C Schaeffer, Clark A Sehon, Robert R Singhaus, Helen H Sun, Barbara A Swift, Rachel D Totoritis, Anna Vossenkämper  1 , Paris Ward, David D Wisnoski, Daohua Zhang, Robert W Marquis, Peter J Gough, John Bertin
Affiliations

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases

Philip A Harris et al. J Med Chem. .

Abstract

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

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