Research Papers:

Identification and Characterization of a Novel Chemotype MEK Inhibitor Able to Alter the Phosphorylation State of MEK1/2

Takayuki Yoshida, Junya Kakegawa, Takayuki Yamaguchi, Yoshiji Hantani, Nobuyuki Okajima, Toshiyuki Sakai, Yoshihiro Watanabe _ and Motonao Nakamura

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Oncotarget. 2012; 3:1533-1545. https://doi.org/10.18632/oncotarget.747

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Takayuki Yoshida1, Junya Kakegawa1, Takayuki Yamaguchi2, Yoshiji Hantani3, Nobuyuki Okajima3, Toshiyuki Sakai4, Yoshihiro Watanabe1,2 and Motonao Nakamura1

1 Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Institute, Japan Tobacco, Kanazawa-ku, Yokohama, Kanagawa, Japan.

2 Biology and Pharmacology Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco, Takatsuki, Osaka, Japan.

3 Chemistry Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco, Takatsuki, Osaka, Japan.

4 Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.


Yoshihiro Watanabe, email:

Keywords: JTP-74057/GSK1120212.trametinib, chemical probe-affinity chromatography, novel MEK inhibitor, unphosphorylated MEK (u-MEK).

Received: November 14, 2012, Accepted: November 30, 2012, Published: December 01, 2012


A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126. It was further shown that JTP-74057 induced rapid and sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines, while this decrease in phosphorylated MEK was not observed in PD0325901-treated cancer cells. Physicochemical analyses revealed that JTP-74057 preferentially binds to unphosphorylated MEK (u-MEK) in unique characteristics of both high affinity based on extremely low dissociation rates and ability stabilizing u-MEK with high thermal shift, which were markedly different from PD0325901. These findings indicate that JTP-74057 is a novel MEK inhibitor able to sustain MEK to be an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation.

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