The discovery of the potent aurora inhibitor MK-0457 (VX-680)

  • Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92. doi: 10.1016/j.bmcl.2009.04.136.
David Bebbington  1 ,  Hayley Binch ,  Jean-Damien Charrier ,  Simon Everitt ,  Damien Fraysse ,  Julian Golec ,  David Kay ,  Ronald Knegtel ,  Chau Mak ,  Francesca Mazzei ,  Andrew Miller ,  Michael Mortimore ,  Michael O'Donnell ,  Sanjay Patel ,  Francoise Pierard ,  Joanne Pinder ,  John Pollard ,  Sharn Ramaya ,  Daniel Robinson ,  Alistair Rutherford ,  John Studley ,  James Westcott
Affiliations
  • 1. Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon OX14 4RY, United Kingdom.
PMID: 19447622 DOI: 10.1016/j.bmcl.2009.04.136
Abstract

The identification of a novel series of Aurora Kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory Chronic Myelogenous Leukemia (CML) or Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL) containing the T315I mutation.