ABSTRACT
PURPOSE: 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.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/prevention & control , Phenylurea Compounds/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Aurora Kinase A , Aurora Kinase B , Aurora Kinase C , Aurora Kinases , Caspase 3/metabolism , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HCT116 Cells , HT29 Cells , HeLa Cells , Histones/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Phenylurea Compounds/chemistry , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Thiazoles/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Subject(s)
Phenylurea Compounds/chemistry , Prodrugs/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Thiazoles/chemistry , Water/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinases , Male , Mice , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
We investigated the applicability of measuring the viscoelasticity of bovine, ovine, and porcine whole blood for the evaluation of sublethal damage to red blood cells (RBCs). An increase in blood viscosity and elasticity without changes in hematocrit and plasma viscosity would signify a decrease in RBC deformability. Blood viscoelasticity was assessed using a Vilastic Scientific viscoelastometer. Due to the natural absence of RBC aggregation and small RBC size in normal bovine and ovine blood, viscoelastic properties are less readily detected. However, we found that adjustment of blood hematocrit to a standard level of 40-50% allows for sensitive assessment of viscoelasticity in these blood types demonstrating a marked non-Newtonian behavior mostly related to RBC deformability. Porcine blood showed a pronounced non-Newtonian behavior at all tested hematocrit values, which makes it rheologically comparable to human blood. Both viscosity and elasticity were elevated after blood exposure to a uniform mechanical stress. RBCs rigidified by heat exposure demonstrated a loss of viscoelasticity dependence on shear rate. Measurements of blood viscoelasticity can be meaningful in bovine, ovine, and, especially, porcine blood, and can be used for evaluation of sublethal blood damage during in vitro and animal trials of heart-assist devices.
