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

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.

• Authors: David Bebbington, 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 13 Pg. 3586-92 (Jul 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19447622 (Publication Type: Journal Article)

Chemical References

• Mutant Proteins
• Piperazines
• Protein Kinase Inhibitors
• tozasertib
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Aurora Kinases
• Cell Line, Tumor
• Computer Simulation
• Crystallography, X-Ray
• Drug Design
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Mutant Proteins (antagonists & inhibitors, metabolism)
• Piperazines (chemistry, pharmacology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship