2. Academic Validation
  3. Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors

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

  • J Med Chem. 2012 Sep 13;55(17):7392-7416. doi: 10.1021/jm300334d.
Harshani R Lawrence 1 2 3,  Matthew P Martin # 1,  Yunting Luo # 2,  Roberta Pireddu # 1,  Hua Yang # 1,  Harsukh Gevariya # 1,  Sevil Ozcan 1,  Jin-Yi Zhu 1,  Robert Kendig 2,  Mercedes Rodriguez 2 1,  Roy Elias 1,  Jin Q Cheng 4 3,  Saïd M Sebti 1 3 5,  Ernst Schonbrunn 1 2 3,  Nicholas J Lawrence 1 3
Affiliations

Affiliations

  • 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.
PMID: 22803810 DOI: 10.1021/jm300334d
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.

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