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

  • ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065.
Amy C Hart  1 ,  Lynn Abell  1 ,  Junqing Guo  1 ,  Michael E Mertzman  1 ,  Ramesh Padmanabha  1 ,  John E Macor  1 ,  Charu Chaudhry  1 ,  Hao Lu  1 ,  Kevin O'Malley  1 ,  Patrick J Shaw  1 ,  Carolyn Weigelt  1 ,  Matthew Pokross  1 ,  Kevin Kish  1 ,  Kyoung S Kim  1 ,  Lyndon Cornelius  1 ,  Andrew E Douglas  1 ,  Deepa Calambur  1 ,  Ping Zhang  1 ,  Brian Carpenter  1 ,  William J Pitts  1
Affiliations
  • 1. Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 32184955 DOI: 10.1021/acsmedchemlett.9b00065
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.

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