title: Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, 10055, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, 10055, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000737:chemistry / Q000187:drug effects*; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6