ヨゴサワ　シンゴ   YOGOSAWA Shingo   与五沢　真吾    所属   埼玉医科大学  保健医療学部 臨床検査学科    職種   准教授
論文種別	学術雑誌(原著)
言語種別	英語
査読の有無	査読あり
表題	Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor
掲載誌名	正式名：CANCER SCIENCE ISSNコード：1347-9032
出版社	BLACKWELL PUBLISHING
巻・号・頁	98(11),1809-1816頁
著者・共著者	Takayuki Yamaguchi,Takayuki Yoshida,Reina Kurachi,Junya Kakegawa,Yoshikazu Hori,Toyomichi Nanayama,Kazuhide Hayakawa,Hiroyuki Abe,Koichi Takagi,Youichirou Matsuzaki,Makoto Koyama,Shingo Yogosawa,Yoshihiro Sowa,Takao Yamori,Nobuyuki Tajima,Toshiyuki Sakai
発行年月	2007/11
概要	The INK4 family members p16(INK4a) and p15(INK4b) negatively regulate cell cycle progression by inhibition of cyclin-dependent kinase (CDK) 4/6. Loss of p16(INK4a) functional activity is frequently observed in tumor cells, and is thought to be one of the primary causes of carcinogenesis. In contrast, despite the biochemical similarity to p16(INK4a), the frequency of defects in p15(INK4b) was found to be lower than in p16(INK4a), suggesting that p15(INK4b)-inductive agents may be useful for tumor suppression. Here we report the discovery of a novel pyrido-pyrimidine derivative, JTP-70902, which exhibits p15(INK4b)-inducing activity in p16(INK4a)-inactivated human colon cancer HT-29 cells. JTP-70902 also induced another CDK-inhibitor, p27(KIP1), and downregulated the expression of c-Myc and cyclin D1, resulting in G(1) cell cycle arrest. MEK1/2 was identified by compound-immobilized affinity chromatography as the molecular target of JTP-70902, and this was further confirmed by the inhibitory activity of JTP-70902 against MEK1/2 in kinase assays. JTP-70902 suppressed the growth of most colorectal and some other cancer cell lines in vitro, and showed antitumor activity in an HT-29 xenograft model. However, JTP-70902 did not inhibit the growth of COLO320 DM cells; in these, constitutive extracellular signal-regulated kinase phosphorylation was not detected, and neither p15(INK4b) nor p27(KIP1) induction was observed. Moreover, p15(INK4b)-deficient mouse embryonic fibroblasts were found to be more resistant to the growth-inhibitory effect of JTP-70902 than wild-type mouse embryonic fibroblasts. These findings suggest that JTP-70902 restores CDK inhibitor-mediated cell cycle control by inhibiting MEK1/2 and exerts a potent antitumor effect.
DOI	10.1111/j.1349-7006.2007.00604.x
NAID	10020119466
PMID	17784872