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
  • 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.