National Center for
4DEB: Aurora A In Complex With Rk2-17-01
Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors
J. Med. Chem. (2012) 55 p.7392-7416
The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 +/- 1.0 nM) from in-house screening. Detailed structure-activity 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-activity 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.