ABSTRACT
2,2'-Bipyridine-terminated poly(dimethylsiloxane)s (bpyPDMS) with number average molecular weights, MN, of 3300, 6100, 26 200, and 50 000 g mol-1 were synthesized. When mixed with Fe(BF4)2 at low concentrations, red solutions formed with UV-vis spectra that match those of iron(ii) tris(2,2'-bipyridine) (Fe(bpy)32+). Upon solvent evaporation, Fe(bpy)32+ crosslinked PDMS networks (bpyPDMS/Fe(ii)) formed, and were studied using oscillating shear rheometry. The shear storage moduli (0.084 to 2.6 MPa) were found to be inversely proportional to the MN of the PDMS, though the storage moduli at low molecular weights greatly exceeded the storage moduli of comparable covalently crosslinked PDMS networks. The shear storage moduli exhibited the characteristic rubbery plateau up to â¼135 °C. Films of bpyPDMS/Fe(ii) coated onto electrodes were found to be electrochemically active, especially so when the PDMS MN is low. The Fe(bpy)32+ crosslinks can be reversibly oxidized over â¼500 nm away from the electrode surface in the presence of a suitable electrolyte.
ABSTRACT
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Subject(s)
Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Aurora Kinases , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
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.