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

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

  • J Med Chem. 2025 Nov 13;68(21):23050-23077. doi: 10.1021/acs.jmedchem.5c01891.
Snahel Patel 1,  Huifen Chen 1,  Eugene Varfolomeev 2,  Youngsu Kwon 3,  Sreemathy Ramaswamy 4,  Pawan Bir Kohli 4,  John G Quinn 4,  Joshua D Webster 5,  Jialin Mao 6,  Yuan Chen 6,  Rina Fong 7,  F Esra Demircioglu 7,  Patrick Lupardus 7,  Craig Stivala 1,  Gregory L Hamilton 1,  Michael Siu 1,  Swathi Sujatha-Bhaskar 2,  Vishnu Mohanan 8,  Adeyemi O Adedeji 9,  Sara F Santagostino 9,  Jonathan Maher 9,  Brent McKenzie 3,  Michael E Rothenberg 10,  Adam Johnson 4,  Domagoj Vucic 2
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Genentech, South San Francisco, California 94080, United States.
  • 2 Department of Immunology Discovery, Genentech, South San Francisco, California 94080, United States.
  • 3 Department of Translational Immunology, Genentech, South San Francisco, California 94080, United States.
  • 4 Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, United States.
  • 5 Department of Pathology, Genentech, South San Francisco, California 94080, United States.
  • 6 Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California 94080, United States.
  • 7 Department of Structural Biology, Genentech, South San Francisco, California 94080, United States.
  • 8 Department of Translational Medicine, Genentech, South San Francisco, California 94080, United States.
  • 9 Department of Translational Safety, Genentech, South San Francisco, California 94080, United States.
  • 10 Department of Early Clinical Development, Genentech, South San Francisco, California 94080, United States.
PMID: 41165210 DOI: 10.1021/acs.jmedchem.5c01891
Abstract

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.

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