sns-314 and Neoplasms

Aurora kinases are serine and threonine kinases that function as key regulators of the mitosis process. There are three distinct human aurora kinases known as Aurora A, Aurora B, and Aurora C. Aurora A and Aurora B are overexpressed in a number of human cancers including non-small cell lung cancer, glioblastomas, and upper gastrointestinal adenocarcinomas. Given their association with tumorigenesis, both Aurora A and Aurora B have been targeted for cancer therapy. Currently, a number of selective and nonselective aurora kinase inhibitors are being tested in preclinical and clinical settings as anti-tumor agents. We review the biology of human aurora kinases, followed by an overview of inhibitors undergoing current clinical investigations.

Topics: Antineoplastic Agents; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Benzamides; Benzimidazoles; Cyclohexanecarboxylic Acids; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Neoplasms; Organophosphates; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Quinazolines; Thiazoles; Urea

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.. 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.. 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.. 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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Caspase 3; Cell Cycle; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; HCT116 Cells; HeLa Cells; Histones; HT29 Cells; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Molecular Structure; Neoplasms; Phenylurea Compounds; Phosphorylation; Protein Serine-Threonine Kinases; Thiazoles; Tumor Burden; Xenograft Model Antitumor Assays