Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.
ACS Med Chem Lett
; 11(3): 266-271, 2020 Mar 12.
Article
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| MEDLINE
| ID: mdl-32184955
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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1
Base de datos:
MEDLINE
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos