Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors
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.
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.
p. 7392 - 7416
(2012/11/07)
AURORA KINASE INHIBITORS AND METHODS OF MAKING AND USING THEREOF
Described herein are inhibitors of Aurora kinase and their use in the treatment of cancer. Methods of screening for selective inhibitors of Aurora kinases are also disclosed.
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Page/Page column 89-90
(2012/10/18)
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