Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors
Document Type
Article
Publication Date
2012
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–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.
Digital Object Identifier (DOI)
https://doi.org/10.1021/jm300334d
Citation / Publisher Attribution
Journal of Medicinal Chemistry, v. 55, issue 17, p. 7392-7416
Scholar Commons Citation
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, Saïd M.; Schonbrunn, Ernst; and Lawrence, Nicholas J., "Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors" (2012). Oncologic Sciences Faculty Publications. 48.
https://digitalcommons.usf.edu/onc_facpub/48
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