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10.1007/s12154-017-0169-9 http://scihub22266oqcxt.onion/10.1007/s12154-017-0169-9 C5480263!5480263 !28684999     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28684999 &cmd=llinks): Failed to open stream: HTTP request failed! 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Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines |pdf=|usr=}}{{28684999 }} gab.com Text Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines JO: J Chem Biol http://www.kidney.de/pget.php?&tw=1&pmid=28684999 #FOAvip Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6R?-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-X(L) STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y(905)) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6R?/gp130 signaling complex that occurs after IL-6 binding to IL-6R? subunits. Twit Text FOAVip Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines ????J Chem Biol http://www.kidney.de/pget.php?&tw=1&pmid=28684999 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28684999 #FOAvip English Wikipedia <ref>{{Cite pmid|28684999 }}</ref> Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines #MMPMID28684999 Sen M ; Johnston PA ; Pollock NI ; DeGrave K ; Joyce SC ; Freilino ML ; Hua Y ; Camarco DP ; Close DA ; Huryn DM ; Wipf P ; Grandis JR J Chem Biol 2017[Jul]; 10 (3 ): 129-141 PMID28684999 show ga Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6R?-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-X(L) STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y(905)) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6R?/gp130 signaling complex that occurs after IL-6 binding to IL-6R? subunits. äMechanism of action of selective inhibitors of IL-6 induced STAT3 path(epmc).pdf DeepDyve Pubget Overpricing