Discovery of novel src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma

Authors

  • Wei-Tien Tai,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
    2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Chung-Wai Shiau,

    1. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Pei-Jer Chen,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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  • Pei-Yi Chu,

    1. Department of Pathology, St. Martin De Porres Hospital, Chiayi, Taiwan
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  • Hsiang-Po Huang,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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  • Chun-Yu Liu,

    1. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
    2. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Jui-Wen Huang,

    1. Industrial Technology Research Institute, Hsin-Chu, Taiwan
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  • Kuen-Feng Chen

    Corresponding author
    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
    2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
    • Address reprint requests to: Kuen-Feng Chen, M.D., Ph.D., Department of Medical Research, National Taiwan University Hospital, No. 7, Chung-Shan S. Rd., Taipei 10055, Taiwan. E-mail: kfchen1970@ntu.edu.tw; Tel: +886-2-23123456, ext: 63548; fax: +886-2-23225329.

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  • Potential conflict of interest: Nothing to report.

Abstract

Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP-1 agonists that may act as better anti-HCC agents than sorafenib. Sorafenib increases SHP-1 activity by direct interaction and impairs the association between the N-SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of sorafenib on SHP-1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and apoptosis, suggesting that sorafenib may affect SHP-1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP-1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC-43 and SC-40 displayed more potent anti-HCC activity than sorafenib, as measured by enhanced SHP-1 activity, inhibition of p-STAT3, and induction of apoptosis. SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors. Conclusion: In this study, we identified SHP-1 as a major target of sorafenib. SC-43 and SC-40, potent SHP-1 agonists, showed better anti-HCC effects than sorafenib in vitro and in vivo. Further clinical investigation is warranted. (Hepatology 2014;58:190–201)

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