Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage
2019
Necroptosishas 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
triagestage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein
crystallography. Structure-based
drug designon the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.
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