Discovery of Pyrrole-Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

被引：51

作者：

Chiang, Chao-Cheng ^{[1
]}

Lin, Yu-Hsiang ^{[1
]}

Lin, Shu Fu ^{[1
]}

Lai, Chun-Liang ^{[1
]}

Liu, Chiawei ^{[1
]}

Wei, Win-Yin ^{[1
]}

Yang, Sheng-chuan ^{[1
]}

Wane, Ru-Wen ^{[1
]}

Teng, Li-Wei ^{[1
]}

Chuang, Shih-Hsien ^{[1
]}

Chang, Jia-Ming ^{[1
]}

Yuan, Ta-Tung ^{[1
]}

Lee, Ying-Shuen ^{[1
]}

Chen, Paonien ^{[1
]}

Chi, Wei-Kuang ^{[1
]}

Yang, Ju-Ying ^{[1
]}

Huang, Hung-Jyun ^{[1
]}

Liao, Chu-Bin ^{[1
]}

Huang, Jiann-Jyh ^{[1
]}

机构：

[1] Dev Ctr Biotechnol, Xizhi City, Taipei County, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 16期

关键词：

RECEPTOR TYROSINE KINASES; SMALL-MOLECULE INHIBITOR; STRUCTURAL BASIS; B KINASE; IN-VIVO; POTENT; CANCER; DESIGN; INDOLIN-2-ONES; SELECTIVITY;

D O I：

10.1021/jm1001869

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC(50) values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC(50) = 2.19 mu M). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.

引用

页码：5929 / 5941

页数：13

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