Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.
Basic Information
ID: ALA4342476
Journal: ACS Med Chem Lett
Title: Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.
Authors: Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ.
Abstract: Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.
CiteXplore: 32184955
DOI: 10.1021/acsmedchemlett.9b00065
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