Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)

被引：42

作者：

Kusakabe, Ken-ichi ^{[1
]}

Ide, Nobuyuki ^{[1
]}

Daigo, Yataro ^{[4
,5
]}

Tachibana, Yuki ^{[1
]}

Itoh, Takeshi ^{[1
]}

Yamamoto, Takahiko ^{[3
]}

Hashizume, Hiroshi ^{[1
]}

Hato, Yoshio ^{[1
]}

Higashino, Kenichi ^{[3
]}

Okano, Yousuke ^{[3
]}

Sato, Yuji ^{[1
]}

Inoue, Makiko ^{[1
]}

Iguchi, Motofumi ^{[1
]}

Kanazawa, Takayuki ^{[1
]}

Ishioka, Yukichi ^{[1
]}

Dohi, Keiji ^{[1
]}

Kido, Yasuto ^{[2
]}

Sakamoto, Shingo ^{[2
]}

Yasuo, Kazuya ^{[3
]}

Maeda, Masahiro ^{[3
]}

Higaki, Masayo ^{[3
]}

Ueda, Kazuo ^{[1
]}

Yoshizawa, Hidenori ^{[1
]}

Baba, Yoshiyasu ^{[1
]}

Shiota, Takeshi ^{[1
]}

Murai, Hitoshi ^{[1
]}

Nakamura, Yusuke ^{[4
]}

机构：

[1] Shionogi Pharmaceut Res Ctr, Med Res Labs, Toyonaka, Osaka 5610825, Japan

[2] Shionogi Pharmaceut Res Ctr, Drug Dev Res Labs, Toyonaka, Osaka 5610825, Japan

[3] Shionogi Pharmaceut Res Ctr, Innovat Drug Discovery Res Labs, Toyonaka, Osaka 5610825, Japan

[4] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med,Minato Ku, Tokyo 1088639, Japan

[5] Shiga Univ Med Sci, Dept Med Oncol, Otsu, Shiga 5202192, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 11期

基金：

日本学术振兴会;

关键词：

SPINDLE ASSEMBLY CHECKPOINT; MITOTIC CHECKPOINT; PROTEIN-KINASE; CANCER-CELLS; CENTROSOME DUPLICATION; GENETIC INSTABILITY; EXPRESSION; ANEUPLOIDY; CONFORMATION; HOMOLOG;

D O I：

10.1021/jm4000215

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

引用

页码：4343 / 4356

页数：14

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