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

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

Affiliation

  • 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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