1395886-77-7Relevant articles and documents
Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors
Lawrence, Harshani R.,Martin, Mathew P.,Luo, Yunting,Pireddu, Roberta,Yang, Hua,Gevariya, Harsukh,Ozcan, Sevil,Zhu, Jin-Yi,Kendig, Robert,Rodriguez, Mercedes,Elias, Roy,Cheng, Jin Q.,Sebti, Sa?d M.,Schonbrunn, Ernst,Lawrence, Nicholas J.
supporting information, p. 7392 - 7416 (2012/11/07)
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 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.
