Document Report Card

ID: ALA3351461

Journal: J Med Chem

Title: Discovery of novel, dual mechanism ERK inhibitors by affinity selection screening of an inactive kinase.

Authors: Deng Y, Shipps GW, Cooper A, English JM, Annis DA, Carr D, Nan Y, Wang T, Zhu HY, Chuang CC, Dayananth P, Hruza AW, Xiao L, Jin W, Kirschmeier P, Windsor WT, Samatar AA.

Abstract: 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.

CiteXplore: 25313996

DOI: 10.1021/jm500847m