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

作者：Chiang Chao Cheng; Lin Yu Hsiang; Lin Shu Fu; Lai Chun Liang; Liu Chiawei; Wei Win Yin; Yang Sheng chuan; Wane Ru Wen; Teng Li Wei; Chuang Shih Hsien; Chang Jia Ming; Yuan Ta Tung; Lee Ying Shuen; Chen Paonien; Chi Wei Kuang; Yang Ju Ying; Huang Hung Jyun; Liao Chu Bin; Huang Jiann Jyh^*

来源：Journal of Medicinal Chemistry, 2010, 53(16): 5929-5941.

DOI：10.1021/jm1001869

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.

• 出版日期2010-8-26