title: Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity.
abstract: Previously, we demonstrated that the multiple kinase inhibitor sorafenib mediates the repression of phospho-STAT3 in hepatocellular carcinoma cells. In this study, we used this kinase-independent mechanism as a molecular basis to use sorafenib as scaffold to develop a novel class of SHP-1-activating agents. The proof of principle of this premise was provided by SC-1, which on replacement of N-methylpicolinamide by a phenylcyano group showed abolished kinase activity while retaining phospho-STAT3 repressive activity. Structural optimization of SC-1 led to compound 6, which repressed phospho-STAT3 through SHP-1 activation and inhibited PLC5 cell proliferation at sub-micromolar potency. In light of the pivotal role of phospho-STAT3 in promoting tumorigenesis and drug resistance, this novel SHP-1-activating agent may have therapeutic relevance in cancer therapy.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Hsu
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: InKi
authors.initials: I
authors.lastname: Kim
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010750:Phosphoproteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib; D011494:Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6