Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2.

T. Yoshida, J. Kakegawa, T. Yamaguchi, Y. Hantani, N. Okajima, T. Sakai, Y. Watanabe, and M. Nakamura

Abstract
A small molecule compound JTP-74057 (GSK1120212) was generated as a very potent
antiproliferative agent that targets various cancer cells by inducing G1 cell cycle arrest via the
accumulation of the CDK inhibitor p15INK4b. Biochemical studies using JTP-74057 derivatives
and enzymatic analyses showed that JTP-74057 directly binds to MEK1 and MEK2 and
allosterically inhibits their kinase activities. It was also shown that JTP-74057 induces rapid and
sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines.
Fluorescence correlation spectroscopy and surface plasmon resonance analyses revealed that
JTP-74057 binds to unphosphorylated MEK with high affinity and a very low dissociation rate.
These results indicate that JTP-74057 is a novel MEK inhibitor that provides sustained levels of
unphosphorylated MEK, resulting in pronounced suppression of downstream signaling
pathways involved in cellular proliferation.

Oncotarget

3

1533

1545