Abstract
Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Animals, Outbred Strains
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / blood
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Biological Availability
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Evaluation, Preclinical
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Drugs, Investigational / administration & dosage
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Drugs, Investigational / analysis
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Drugs, Investigational / pharmacokinetics
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Drugs, Investigational / pharmacology*
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Half-Life
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Humans
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Male
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Neoplasms / blood
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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Niacinamide / administration & dosage
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Niacinamide / analogs & derivatives*
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Niacinamide / blood
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Niacinamide / pharmacokinetics
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Niacinamide / pharmacology
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Phenylurea Compounds / administration & dosage
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Phenylurea Compounds / blood
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Phenylurea Compounds / pharmacokinetics
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Phenylurea Compounds / pharmacology*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / blood
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Resting Phase, Cell Cycle / drug effects
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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raf Kinases / antagonists & inhibitors*
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raf Kinases / metabolism
Substances
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Antineoplastic Agents
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Drugs, Investigational
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Neoplasm Proteins
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Phenylurea Compounds
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Protein Kinase Inhibitors
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trans-4-(4-(3-(4-chloro-3-trifluoromethylphenyl)-ureido)-cyclohexyloxy-pyridine-2-carboxylic acid methylamide
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Niacinamide
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
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raf Kinases