VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.
Vertex Pharmaceuticals (Europe) Limited, 88 Milton Park, Abingdon, Oxfordshire, OX14 4RY, UK.
Elizabeth A
EA
Harrington
David
D
Bebbington
Jeff
J
Moore
Richele K
RK
Rasmussen
Abi O
AO
Ajose-Adeogun
Tomoko
T
Nakayama
Joanne A
JA
Graham
Cecile
C
Demur
Thierry
T
Hercend
Anita
A
Diu-Hercend
Michael
M
Su
Julian M C
JM
Golec
Karen M
KM
Miller
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064127:Aurora Kinases; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064127:Aurora Kinases; D004791:Enzyme Inhibitors; D006657:Histones; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines