title: Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf.
abstract: STAT3 is a transcription factor that modulates survival-directed transcription. It is persistently activated in many human cancers. Literature has shown that sorafenib, Raf kinase inhibitor, reduces Phospho-STAT3 and induces cell death. A series of sorafenib derivatives were synthesized as new inhibitors for STAT3. Urea, sulfonamide, and carboxamide linkers brought out different SARs from the end of sorafenib. Urea and carboxamide linked derivatives showed greater inhibition against STAT3 activity than sulfonamide linked derivatives. In particular, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-cyanophenoxy)phenyl)urea (1), a urea linker, was as potent as sorafenib in reducing P-STAT3 level and cell death but no inhibition for Raf activity. Such result provides a new lead for the design of STAT3 inhibitors.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, Taiwan, Republic of China.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Hsu
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chen
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D000577:Amides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014508:Urea / Q000737:chemistry; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D009536:Niacinamide; D014508:Urea; D000077157:Sorafenib; D048490:raf Kinases