https://scholars.lib.ntu.edu.tw/handle/123456789/565026
標題: | Discovery of novel src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma | 作者: | Tai W.-T. Shiau C.-W. PEI-JER CHEN Chu P.-Y. HSIANG-PO HUANG Liu C.-Y. Huang J.-W. Chen K.-F. |
公開日期: | 2014 | 出版社: | John Wiley and Sons Inc. | 卷: | 59 | 期: | 1 | 起(迄)頁: | 190-201 | 來源出版物: | Hepatology | 摘要: | 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. ? 2013 by the American Association for the Study of Liver Diseases. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84894731135&doi=10.1002%2fhep.26640&partnerID=40&md5=9a805e2367a49b22bfb65b990c865ff1 https://scholars.lib.ntu.edu.tw/handle/123456789/565026 |
ISSN: | 0270-9139 | DOI: | 10.1002/hep.26640 | SDG/關鍵字: | antineoplastic agent; protein SH2; protein tyrosine phosphatase SHP 1; protein tyrosine phosphatase SHP 1 agonist; sc 40; sc 43; sorafenib; sorafenib derivative; STAT3 protein; unclassified drug; antineoplastic agent; carbanilamide derivative; drug derivative; nicotinamide; protein tyrosine phosphatase SHP 1; sorafenib; STAT3 protein; antineoplastic agent; carbanilamide derivative; nicotinamide; protein tyrosine phosphatase SHP 1; animal experiment; animal model; antineoplastic activity; apoptosis; Article; cancer inhibition; complex formation; concentration response; conformational transition; controlled study; dose response; drug cytotoxicity; drug effect; drug mechanism; drug potency; drug targeting; enzyme activity; enzyme inhibition; hepatocellular carcinoma cell line; human; human tissue; immunohistochemistry; in vitro study; in vivo study; liver cell carcinoma; molecular docking; mouse; nonhuman; point mutation; priority journal; protein domain; protein expression; animal; article; chemical structure; chemistry; drug antagonism; drug resistance; drug screening; enzyme active site; liver cell carcinoma; liver tumor; randomization; tumor cell line; analogs and derivatives; antagonists and inhibitors; Carcinoma, Hepatocellular; drug effects; Liver Neoplasms; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Catalytic Domain; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Mice; Models, Molecular; Niacinamide; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Random Allocation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Catalytic Domain; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Mice; Models, Molecular; Niacinamide; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Random Allocation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays |
顯示於: | 基因體暨蛋白體醫學研究所 |
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