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Title of Journal: Cancer Chemother Pharmacol

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Abbravation: Cancer Chemotherapy and Pharmacology

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Springer-Verlag

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DOI

10.1016/0022-1902(73)80088-0

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1432-0843

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SNS314 a panAurora kinase inhibitor shows pote

Authors: Jennifer P Arbitrario Brian J Belmont Marc J Evanchik W Michael Flanagan Raymond V Fucini Stig K Hansen Shannon O Harris Ahmad Hashash Ute Hoch Jennifer N Hogan Anthony R Howlett Jeffrey W Jacobs Joni W Lam Sean C Ritchie Michael J Romanowski Jeffrey A Silverman David E Stockett Juli N Teague Kristin M Zimmerman Pietro Taverna
Publish Date: 2009/08/01
Volume: 65, Issue: 4, Pages: 707-717
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Abstract

The Aurora family of serine/threonine kinases AuroraA AuroraB and AuroraC 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 SNS314 an ATPcompetitive selective and potent inhibitor of Aurora kinasesWe studied the biochemical potency and selectivity of SNS314 to inhibit Aurora kinases A B and C The inhibition of cellular proliferation induced by SNS314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation inhibition of cellcycle progression increase in nuclear content and cell size loss of viability and induction of apoptosis The dose and administration schedule of SNS314 was optimized for in vivo efficacy in mouse xenograft models of human cancerIn the HCT116 human colon cancer xenograft model administration of 50 and 100 mg/kg SNS314 led to dosedependent inhibition of histone H3 phosphorylation for at least 10 h indicating effective AuroraB inhibition in vivo HCT116 tumors from animals treated with SNS314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels increased caspase3 and appearance of increased nuclear size The compound showed significant tumor growth inhibition in a dosedependent manner under a variety of dosing schedules including weekly biweekly and 5 days on/9 days offThe authors would like to thank for their contributions to the SNS314 project Darrin A Allen Subramanian Baskaran Minna Bui Emily J Hanan Stacey A Heumann Willard Lew Robert S McDowell Johan D Oslob Wang Shen Joshua C Yoburn Chul H Yu and Min Zhong Chemistry Jeffrey Kumer and Tara Mullaney Pharmacology Tom O’Brien and Bradley Tangonan Biology

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