A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B

  • J Med Chem. 2009 May 28;52(10):3300-7. doi: 10.1021/jm9000314.
Ignacio Aliagas-Martin  1 ,  Dan Burdick ,  Laura Corson ,  Jennafer Dotson ,  Jason Drummond ,  Carter Fields ,  Oscar W Huang ,  Thomas Hunsaker ,  Tracy Kleinheinz ,  Elaine Krueger ,  Jun Liang ,  John Moffat ,  Gail Phillips ,  Rebecca Pulk ,  Thomas E Rawson ,  Mark Ultsch ,  Leslie Walker ,  Christian Wiesmann ,  Birong Zhang ,  Bing-Yan Zhu ,  Andrea G Cochran
Affiliations
  • 1. Department of Small Molecule Drug Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
PMID: 19402633 DOI: 10.1021/jm9000314
Abstract

The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.

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