title: Novel carbazole inhibits phospho-STAT3 through induction of protein-tyrosine phosphatase PTPN6.
abstract: The aberrant activation of STAT3 occurs in many human cancers and promotes tumor progression. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3. Synthesized carbazole derived with fluorophore compound 12 was discovered to target STAT3 phosphorylation. Compound 12 was found to inhibit STAT3-mediated transcription as well as to reduce IL-6 induced STAT3 phosphorylation in cancer cell lines expressing both elevated and low levels of phospho-STAT3 (Y705). Compound 12 potently induced apoptosis in a broad number of TNBC cancer cell lines in vitro and was effective at inhibiting the in vivo growth of human TNBC xenograft tumors (SUM149) without any observed toxicity. Compound 12 also effectively inhibited the growth of human lung tumor xenografts (A549) harboring aberrantly active STAT3. In vitro and in vivo studies showed that the inhibitory effects of 12 on phospho-STAT3 were through up-regulation of the protein-tyrosine phosphatase PTPN6. Our present studies strongly support the continued preclinical evaluation of compound 12 as a potential chemotherapeutic agent for TNBC and cancers with constitutive STAT3 signaling.
authors: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road, NW, Washington, D.C., 20057, United States.
authors: Shujie
authors: S
authors: Hou
authors: Yong Weon
authors: YW
authors: Yi
authors: Hyo Jin
authors: HJ
authors: Kang
authors: Li
authors: L
authors: Zhang
authors: Hee Jeong
authors: HJ
authors: Kim
authors: Yali
authors: Y
authors: Kong
authors: Yong
authors: Y
authors: Liu
authors: Kan
authors: K
authors: Wang
authors: Hye-Sik
authors: HS
authors: Kong
authors: Scott
authors: S
authors: Grindrod
authors: Insoo
authors: I
authors: Bae
authors: Milton L
authors: ML
authors: Brown
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction; D005260:Female; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009282:Naphthalenesulfonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: C000594980:7-hydroxy-1-methyl-9H-carbazol-2-yl 5-(dimethylamino)naphthalene-1-sulfonate; D000970:Antineoplastic Agents; D002227:Carbazoles; D015850:Interleukin-6; D009282:Naphthalenesulfonates; D050796:STAT3 Transcription Factor; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6