{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:28:53Z","timestamp":1777523333608,"version":"3.51.4"},"reference-count":70,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["ASSAY and Drug Development Technologies"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:p>\n                    Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and\/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC\n                    <jats:sub>50<\/jats:sub>\n                    assays, and an IFN\u03b3-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC\n                    <jats:sub>50<\/jats:sub>\n                    s against IFN-\u03b3-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by \u226570% at 20\u2009\u03bcM; their pSTAT3 activation IC\n                    <jats:sub>50<\/jats:sub>\n                    s were \u226425\u2009\u03bcM; they were \u22652-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were \u226590% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC\n                    <jats:sub>50<\/jats:sub>\n                    s \u226420\u2009\u03bcM and 13 were \u22653-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC\n                    <jats:sub>50<\/jats:sub>\n                    s \u2264 20\u2009\u03bcM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole\u2013piperazine singleton.\n                  <\/jats:p>","DOI":"10.1089\/adt.2015.663","type":"journal-article","created":{"date-parts":[[2015,8,28]],"date-time":"2015-08-28T16:11:54Z","timestamp":1440778314000},"page":"356-376","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines"],"prefix":"10.1177","volume":"13","author":[{"given":"Paul A.","family":"Johnston","sequence":"first","affiliation":[{"name":"University of Pittsburgh"},{"name":"University of Pittsburgh Cancer Institute"},{"name":"University of Pittsburgh Drug Discovery 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