Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase
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- 作者：Yongqi Deng ; Gerald W. Shipps ; Jr. ; Alan Cooper ; Jessie M. English ; D. Allen Annis ; Donna Carr ; Yang Nan ; Tong Wang ; Hugh Y. Zhu ; Cheng-Chi Chuang ; Priya Dayananth ; Alan W. Hruza ; Li Xiao ; Weihong Jin ; Paul Kirschmeier ; William T. Windsor ; Ahmed A. Samatar
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 13, 2014
- 年：2014
- 卷：57
- 期：21
- 页码：8817-8826
- 全文大小：386K
- ISSN：1520-4804
文摘
An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.