title: 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.affiliation: Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon OX14 4RY, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bebbington
authors.forename: Hayley
authors.initials: H
authors.lastname: Binch
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Charrier
authors.forename: Simon
authors.initials: S
authors.lastname: Everitt
authors.forename: Damien
authors.initials: D
authors.lastname: Fraysse
authors.forename: Julian
authors.initials: J
authors.lastname: Golec
authors.forename: David
authors.initials: D
authors.lastname: Kay
authors.forename: Ronald
authors.initials: R
authors.lastname: Knegtel
authors.forename: Chau
authors.initials: C
authors.lastname: Mak
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzei
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.forename: Michael
authors.initials: M
authors.lastname: Mortimore
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donnell
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.forename: Francoise
authors.initials: F
authors.lastname: Pierard
authors.forename: Joanne
authors.initials: J
authors.lastname: Pinder
authors.forename: John
authors.initials: J
authors.lastname: Pollard
authors.forename: Sharn
authors.initials: S
authors.lastname: Ramaya
authors.forename: Daniel
authors.initials: D
authors.lastname: Robinson
authors.forename: Alistair
authors.initials: A
authors.lastname: Rutherford
authors.forename: John
authors.initials: J
authors.lastname: Studley
authors.forename: James
authors.initials: J
authors.lastname: Westcott
mesh_terms: D064127:Aurora Kinases; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D050505:Mutant Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines