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Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.

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.

SUBMITTER: Hart AC

PROVIDER: S-EPMC7073880 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.

Hart Amy C AC Abell Lynn L Guo Junqing J Mertzman Michael E ME Padmanabha Ramesh R Macor John E JE Chaudhry Charu C Lu Hao H O'Malley Kevin K Shaw Patrick J PJ Weigelt Carolyn C Pokross Matthew M Kish Kevin K Kim Kyoung S KS Cornelius Lyndon L Douglas Andrew E AE Calambur Deepa D Zhang Ping P Carpenter Brian B Pitts William J WJ

ACS medicinal chemistry letters 20190506 3

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 previo ...[more]

PMID: 32184955

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