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J Med Chem. 2012 Sep 13;55(17):7392-7416. doi: 10.1021/jm300334d. Epub 2012 Aug 30.

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

Author information

1
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
2
Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
3
Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
4
Department of Molecular Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
5
Department of Molecular Medicine, University of South Florida, Tampa, FL 33620, USA.
#
Contributed equally

Abstract

The o-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.

PMID:
22803810
PMCID:
PMC4429609
DOI:
10.1021/jm300334d
[Indexed for MEDLINE]
Free PMC Article

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