Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage,ACS Medicinal Chemistry Letters

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Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-05-08 , 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

Affiliation

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.

中文翻译：

在命中分类中使用高通量机制研究鉴定RIPK3 II型抑制剂

坏死病涉及多种疾病状态，RIPK3是经鉴定在该信号通路中起关键作用的激酶之一。为了鉴定具有新颖特征的RIPK3激酶抑制剂，在命中分诊阶段纳入了机理研究。这些测定法的使用使得能够鉴定II型DFG-out RIPK3抑制剂，这通过蛋白质晶体学证实。针对靶向该先前未报道的构象的抑制剂的基于结构的药物设计使得对关键脱靶激酶的选择性得以增强。

更新日期：2019-11-18

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