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

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

Affiliation

  • 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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