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

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.

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers

“…GSK2982772 inhibited RIPK1 activity in blood, in a concentration‐dependent manner, as measured by the inhibition of MIP‐1α and MIP‐1β production in an ex vivo challenge assay . The level of GSK2982772 binding to RIPK1 in blood, measured by the TE assay, exhibited a similar concentration‐dependent profile.…”

“…These cytokine levels were analyzed following ex vivo stimulation of cells with a stimulation cocktail in TruCulture (Myriad RBM, Austin, TX, USA) tubes (unpublished data on file, GlaxoSmithKline, Collegeville, PA). Whole blood (1 mL) was drawn into TruCulture tubes containing 2 mL of stimulation cocktail (medium containing TNF, zVAD, and SMAC mimetic) and incubated for 6 hours at 37°C . The assay was optimized in preclinical studies by pretreating whole blood with GSK2982772 for 1 hour and then transferring 1 mL of the treated blood to TruCulture tubes containing stimulation cocktail in 2 mL of media.…”

“…The assay was optimized in preclinical studies by pretreating whole blood with GSK2982772 for 1 hour and then transferring 1 mL of the treated blood to TruCulture tubes containing stimulation cocktail in 2 mL of media. Plasma was separated and concentrations of MIP‐1α and MIP‐1β were quantified using the Meso Scale Discovery platform (Meso Scale Diagnostics, Rockville, MD, USA) …”

Small molecule probes for cellular death machines

“…Different from Nec-1, which occupies a hydrophobic pocket in close proximity to the activation loop of RIPK1 kinase as type III inhibitor[42], these GSK compound series (1-aminoisoquinolines, pyrrolo[2,3-b]pyridines and furo[2,3-d]pyrimidines, represented by Cpd27) bind to the DLG-out inactive conformation as typical type-II inhibitors [43]. GSK has also developed a type III RIPK1 inhibitor GSK2982772, an optimized derivative of benzoxazepinone, and advanced this compound into human clinical trials targeting psoriasis, rheumatoid arthritis, and ulcerative colitis [44,45]. In addition, Denali Therapeutics has advanced a RIPK1 inhibitor into Phase I human clinical trial targeting ALS and AD.…”

Mechanism and disease implications of necroptosis and neuronal inflammation

“…Nevertheless, all of them presented several limitations. GSK2982772, a RIP1-kinase inhibitor, is currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis 10 , which highlights the relevance and importance of pharmacological inhibition of necroptosis in the context of disease.…”