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

• Published in: Journal of medicinal chemistry 2012-08, Vol.55 (17), p.7392-7416
• Main Authors: Lawrence, Harshani R., Martin, Matthew P., Luo, Yunting, Pireddu, Roberta, Yang, Hua, Gevariya, Harsukh, Ozcan, Sevil, Zhu, Jin-Yi, Kendig, Robert, Rodriguez, Mercedes, Elias, Roy, Cheng, Jin Q., Sebti, Saïd M., Schonbrunn, Ernst, Lawrence, Nicholas J.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300334d

The ortho -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.