title: SC-60, a dimer-based sorafenib derivative, shows a better anti-hepatocellular carcinoma effect than sorafenib in a preclinical hepatocellular carcinoma model.
abstract: Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma. Here, we report that SC-60, a dimer-based sorafenib derivative, overcomes the resistance of sorafenib and shows a better anti-hepatocellular carcinoma effect in vitro and in vivo. SC-60 substantially increased SH2 domain-containing phosphatase 1 (SHP-1) phosphatase activity in hepatocellular carcinoma cells and purified SHP-1 proteins, suggesting that SC-60 affects SHP-1 directly. Molecular docking and truncated mutants of SHP-1 further confirmed that SC-60 interferes with the inhibitory N-SH2 domain to relieve the closed catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of SC-60 on SHP-1, p-STAT3, and apoptosis. Importantly, SC-60 exhibited significant survival benefits compared with sorafenib in a hepatocellular carcinoma orthotopic model via targeting the SHP-1/STAT3-related signaling pathway. In summary, dimer derivative of sorafenib, SC-60, is a SHP-1 agonist and may be a potent reagent for hepatocellular carcinoma-targeted therapy.
authors.affiliation: Corresponding Author: Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 10016, Taiwan, Republic of China. kfchen1970@ntu.edu.tw.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Yong-Shi
authors.initials: YS
authors.lastname: Li
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Hsu
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Hsu
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000737:chemistry; D017354:Point Mutation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009536:Niacinamide; D000077157:Sorafenib; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6