9q31 | pdb_00009q31
RIP1 kinase domain in complex with GDC-8264
Structural highlights
FunctionRIPK1_HUMAN Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.[1] [2] [3] Publication Abstract from PubMedReceptor-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. Discovery of Clinical Candidate GDC-8264, a Novel, Potent and Selective RIP1 Inhibitor for Amelioration of Tissue Damage and the Treatment of Inflammatory Diseases.,Patel S, Chen H, Varfolomeev E, Kwon Y, Ramaswamy S, Kohli PB, Quinn JG, Webster JD, Mao J, Chen Y, Fong R, Demircioglu FE, Lupardus P, Stivala C, Hamilton GL, Siu M, Sujatha-Bhaskar S, Mohanan V, Adedeji AO, Santagostino SF, Maher J, McKenzie B, Rothenberg ME, Johnson A, Vucic D J Med Chem. 2025 Oct 30. doi: 10.1021/acs.jmedchem.5c01891. PMID:41165210[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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