Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors

• DOI: 10.1021/jm300334d
• Publication Date: 2012-07-18T16:13:56Z
• Authors: 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; Saïd M. Sebti; Ernst Schonbrunn; Nicholas J. Lawrence
• Keywords: Lead compound; Structure–activity relationship; Aurora B kinase; Aurora kinase

The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 ± 1.0 nM) from in-house screening. Detailed structure–activity relationship (SAR) studies indicated that polar substituents at the para position of B-ring are critical for activity. X-ray crystallography revealed compound is type I inhibitor binds Aurora kinase active site in DFG-in conformation. Structure–activity guided replacement A-ring carboxylic with halogens and incorporation fluorine pyrimidine 5-position led to highly inhibitors bind DFG-out B-Ring modifications were undertaken improve solubility cell permeability. Compounds such 9m water-solubilizing moieties inhibited autophosphorylation MDA-MB-468 breast cancer cells.