The discovery of the potent aurora inhibitor MK-0457 (VX-680).
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.
Bebbington
David
D
Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon OX14 4RY, United Kingdom.
Binch
Hayley
H
Charrier
Jean-Damien
JD
Everitt
Simon
S
Fraysse
Damien
D
Golec
Julian
J
Kay
David
D
Knegtel
Ronald
R
Mak
Chau
C
Mazzei
Francesca
F
Miller
Andrew
A
Mortimore
Michael
M
O'Donnell
Michael
M
Patel
Sanjay
S
Pierard
Francoise
F
Pinder
Joanne
J
Pollard
John
J
Ramaya
Sharn
S
Robinson
Daniel
D
Rutherford
Alistair
A
Studley
John
J
Westcott
James
J
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
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