SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo.
OBJECTIVE
The Aurora family of serine/threonine kinases (Aurora-A, Aurora-B, and Aurora-C) plays a key role in cells orderly progression through mitosis. Elevated expression levels of Aurora kinases have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors. We characterized the biological and pharmacological properties of SNS-314, an ATP-competitive, selective, and potent inhibitor of Aurora kinases.


METHODS
We studied the biochemical potency and selectivity of SNS-314 to inhibit Aurora kinases A, B, and C. The inhibition of cellular proliferation induced by SNS-314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation, inhibition of cell-cycle progression, increase in nuclear content and cell size, loss of viability, and induction of apoptosis. The dose and administration schedule of SNS-314 was optimized for in vivo efficacy in mouse xenograft models of human cancer.


RESULTS
In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 led to dose-dependent inhibition of histone H3 phosphorylation for at least 10 h, indicating effective Aurora-B inhibition in vivo. HCT116 tumors from animals treated with SNS-314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. The compound showed significant tumor growth inhibition in a dose-dependent manner under a variety of dosing schedules including weekly, bi-weekly, and 5 days on/9 days off.


CONCLUSIONS
SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.
Arbitrario
Jennifer P
JP
Department of Pharmacology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South S. Francisco, CA 94080, USA.
Belmont
Brian J
BJ
Evanchik
Marc J
MJ
Flanagan
W Michael
WM
Fucini
Raymond V
RV
Hansen
Stig K
SK
Harris
Shannon O
SO
Hashash
Ahmad
A
Hoch
Ute
U
Hogan
Jennifer N
JN
Howlett
Anthony R
AR
Jacobs
Jeffrey W
JW
Lam
Joni W
JW
Ritchie
Sean C
SC
Romanowski
Michael J
MJ
Silverman
Jeffrey A
JA
Stockett
David E
DE
Teague
Juli N
JN
Zimmerman
Kristin M
KM
Taverna
Pietro
P
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006657:Histones; D010671:Phenylurea Compounds; C532454:SNS 314; D013844:Thiazoles; C576921:AURKB protein, human; C576927:AURKC protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; C576928:Aurkc protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3