Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors

…, JY Zhu, R Kendig, M Rodriguez, R Elias…

Index: 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, Said M.; Schonbrunn, Ernst; Lawrence, Nicholas J. Journal of Medicinal Chemistry, 2012 , vol. 55, # 17 p. 7392 - 7416

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Citation Number: 25

Abstract

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 ...