1 research outputs found
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
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 <b>5</b>), currently in phase 2a clinical
studies for psoriasis, rheumatoid arthritis, and ulcerative colitis.
Compound <b>5</b> 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 <b>5</b>, combined with
high potency, led to a predicted low oral dose in humans