Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors
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- 作者：Harshani R. Lawrence ; Mathew P. Martin ; Yunting Luo ; Roberta Pireddu ; Hua Yang ; Harsukh Gevariya ; Sevil Ozcan ; Jin-Yi Zhu ; Robert Kendig ; Mercedes Rodriguez ; Roy Elias ; Jin Q. Cheng ; Sa茂d M. Sebti ; Ernst Schonbrunn ; Nicholas J. Lawrence
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：55
- 期：17
- 页码：7392-7416
- 全文大小：989K
- 年卷期：v.55,no.17(September 13, 2012)
- ISSN：1520-4804
文摘
The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 卤 1.0 nM) from in-house screening. Detailed structure鈥揳ctivity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure鈥揳ctivity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.