Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile.
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 IC50 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 (IC50=2.19 microM). 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.
Chiang
Chao-Cheng
CC
Development Center for Biotechnology, No. 101, Lane 169, Kangning Street, Xizhi City, Taipei County, Taiwan 221, ROC.
Lin
Yu-Hsiang
YH
Lin
Shu Fu
SF
Lai
Chun-Liang
CL
Liu
Chiawei
C
Wei
Win-Yin
WY
Yang
Sheng-chuan
SC
Wang
Ru-Wen
RW
Teng
Li-Wei
LW
Chuang
Shih-Hsien
SH
Chang
Jia-Ming
JM
Yuan
Ta-Tung
TT
Lee
Ying-Shuen
YS
Chen
Paonien
P
Chi
Wei-Kuang
WK
Yang
Ju-Ying
JY
Huang
Hung-Jyun
HJ
Liao
Chu-Bin
CB
Huang
Jiann-Jyh
JJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006657:Histones; D007211:Indoles; D011758:Pyrroles; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases