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Biological evaluation of a novel sorafenib analogue, t-CUPM

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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.

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Abbreviations

HCC:

Hepatocellular carcinoma

t-CUPM:

trans-4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy-pyridine-2-carboxylic acid methylamide

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Acknowledgments

We thank Dr. Michael Praddy of the MCB Imaging Facility for help with collecting and analyzing our immunohistochemical data on the Olympus FV100 laser point scanning microscope. Special thanks to Carol Oxford and the UCD Flow Cytometry Shared Resource facility for help with collecting and analyzing cell cycle data. This work was supported in part by NIEHS Grant ES02710, NIEHS Superfund Grant P42 ES04699, and NIHLB Grant HL059699 (all to B.D.H.). This work was also supported by NIH Grants 5UO1CA86402 (Early Detection Research Network), 1R01CA135401-01A1, and 1R01DK082690-01A1 (all to R.H.W.), and the Medical Service of the US Department of Veterans’ Affairs (R.H.W.). A.T.W. was support by Award No. T32CA108459 from the National Institutes of Health. B.D.H. is a George and Judy Marcus senior fellow of the American Asthma Foundation.

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None declared.

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Authors and Affiliations

  1. Department of Entomology, University of California, Davis, CA, 95616, USA

    Aaron T. Wecksler, Sung Hee Hwang, Jun-Yan Liu, Christophe Morisseau & Bruce D. Hammock

  2. UC Davis Comprehensive Cancer Center, Sacramento, CA, 95817, USA

    Aaron T. Wecksler, Sung Hee Hwang, Jun-Yan Liu, Christophe Morisseau, Jian Wu, Robert H. Weiss & Bruce D. Hammock

  3. Division of Nephrology, Department of Internal Medicine, Davis Medical Center, University of California, Sacramento, CA, 95817, USA

    Hiromi I. Wettersten & Robert H. Weiss

  4. U.S. Department of Veterans’ Affairs Medical Center, Sacramento, CA, 95655, USA

    Robert H. Weiss

  5. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Davis Medical Center, University of California, Sacramento, CA, 95817, USA

    Jian Wu

Authors
  1. Aaron T. Wecksler
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  2. Sung Hee Hwang
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  8. Bruce D. Hammock
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Correspondence to Bruce D. Hammock.

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Wecksler, A.T., Hwang, S.H., Liu, JY. et al. Biological evaluation of a novel sorafenib analogue, t-CUPM. Cancer Chemother Pharmacol 75, 161–171 (2015). https://doi.org/10.1007/s00280-014-2626-2

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  • DOI: https://doi.org/10.1007/s00280-014-2626-2

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