Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase.
Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G(2)/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.
Manfredi
Mark G
MG
Department of Oncology, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. manfredi@mpi.com
Ecsedy
Jeffrey A
JA
Meetze
Kristan A
KA
Balani
Suresh K
SK
Burenkova
Olga
O
Chen
Wei
W
Galvin
Katherine M
KM
Hoar
Kara M
KM
Huck
Jessica J
JJ
LeRoy
Patrick J
PJ
Ray
Emily T
ET
Sells
Todd B
TB
Stringer
Bradley
B
Stroud
Stephen G
SG
Vos
Tricia J
TJ
Weatherhead
Gabriel S
GS
Wysong
Deborah R
DR
Zhang
Mengkun
M
Bolen
Joseph B
JB
Claiborne
Christopher F
CF
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001552:Benzazepines; D004791:Enzyme Inhibitors; C518940:MLN8054; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases