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Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor

Takayuki Yamaguchi1, Takayuki Yoshida, Reina Kurachi

  • 1Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka, Japan.

Cancer Science
|September 6, 2007
PubMed

Insights

A novel compound, JTP-70902, induces the tumor suppressor p15(INK4b) and arrests cell cycle progression. This MEK1/2 inhibitor demonstrates significant antitumor activity in preclinical cancer models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • INK4 family proteins (p16(INK4a), p15(INK4b)) inhibit cyclin-dependent kinase (CDK) 4/6, regulating cell cycle progression.
  • Loss of p16(INK4a) is common in cancer, while p15(INK4b) defects are less frequent, suggesting therapeutic potential for p15(INK4b) induction.
  • Defects in p15(INK4b) are less frequent than p16(INK4a), indicating potential for p15(INK4b)-inductive agents in tumor suppression.

Purpose of the Study:

  • To discover novel agents that induce p15(INK4b) for potential cancer therapy.
  • To investigate the mechanism of action and antitumor efficacy of a newly identified pyrido-pyrimidine derivative, JTP-70902.

Main Methods:

  • Screening for p15(INK4b)-inducing compounds in p16(INK4a)-inactivated colon cancer cells.
  • Affinity chromatography to identify the molecular target of JTP-70902.
  • In vitro cell proliferation assays and in vivo xenograft models to assess antitumor activity.

Main Results:

  • JTP-70902 induced p15(INK4b) and p27(KIP1), downregulated c-Myc and cyclin D1, causing G1 cell cycle arrest.
  • MEK1/2 was identified as the direct molecular target of JTP-70902.
  • JTP-70902 exhibited potent in vitro and in vivo antitumor activity against various cancer cell lines, including colorectal cancer.

Conclusions:

  • JTP-70902 restores CDK inhibitor-mediated cell cycle control by inhibiting MEK1/2.
  • The compound demonstrates significant potential as an antitumor agent, particularly in cancers with intact p15(INK4b) pathways.
  • Targeting MEK1/2 with JTP-70902 offers a promising strategy for cancer therapy.

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