Discovery of Clinical Candidate GDC-8264, a Novel, Potent and Selective RIP1 Inhibitor for Amelioration of Tissue Damage and the Treatment of Inflammatory Diseases

Receptor-interacting protein 1 (RIP1) is a critical regulator of inflammatory cell death induced by diverse stimuli including TNF family ligands and ischemic injury. As such, the inhibition of RIP1 with small molecule kinase inhibitors is predicted to ameliorate tissue damage and associated inflammation. A novel ketone class of RIP1 inhibitors was identified via a high-throughput screen followed by structure-based scaffold hopping. Subsequent optimization yielded clinical molecule GDC-8264 (compound 19), which has excellent target selectivity and druglike attributes for once-daily oral dosing. GDC-8264 is currently being tested in a Phase 2 trial for the prevention of cardiac surgery-associated acute kidney injury (CSA-AKI) in hopes of providing benefit for patients requiring cardio-pulmonary bypass at medium to high risk of developing CSA-AKI.