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Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 May 06; Vol. 11 (3), pp. 266-271. Date of Electronic Publication: 2019 May 06 (Print Publication: 2020). - Publication Year :
- 2019
-
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.<br />Competing Interests: The authors declare no competing financial interest.<br /> (Copyright © 2019 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 11
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 32184955
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.9b00065