Open AccessIdentification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage
Author(s) -
Amy C. Hart,
Lynn M. Abell,
Junqing Guo,
Michael Mertzman,
Ramesh Padmanabha,
John E. Macor,
Charu Chaudhry,
Hao Lü,
K O’Malley,
Patrick J. Shaw,
Carolyn A. Weigelt,
Matthew Pokross,
Kevin Kish,
Kyoung S. Kim,
Lyndon Cornelius,
Andrew Douglas,
Deepa Calambur,
Ping Zhang,
Brian Carpenter,
William J. Pitts
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00065
Subject(s) - necroptosis , kinase , identification (biology) , computational biology , drug discovery , triage , computer science , bioinformatics , medicine , chemistry , biology , biochemistry , programmed cell death , medical emergency , botany , apoptosis
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.