1. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage
- Author
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Charu Chaudhry, Ping Zhang, Kyoung S. Kim, William J. Pitts, Cornelius Lyndon A M, Lynn M. Abell, Hart Amy C, Kevin O’Malley, Junqing Guo, Brian Carpenter, Hao Lu, Ramesh Padmanabha, Patrick J. Shaw, Mertzman Michael E, Kevin Kish, Andrew E Douglas, Matthew Pokross, John E. Macor, Deepa Calambur, and Carolyn A. Weigelt
- Subjects
010405 organic chemistry ,Kinase ,Chemistry ,Necroptosis ,Organic Chemistry ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Discovery ,Transferase ,Identification (biology) ,Signal transduction - Abstract
[Image: see text] 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.
- Published
- 2019