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Current therapies for Gli\u2010driven tumors target Smoothened (SMO), a G protein\u2010coupled receptor\u2010like protein that functions upstream in the Hh pathway. Although these drugs can have remarkable clinical efficacy, mutations in SMO and downstream Hh pathway components frequently lead to chemoresistance. In principle, therapies that act at the level of Gli proteins, through direct or indirect mechanisms, would be more efficacious. We therefore screened 325\u2009120 compounds for their ability to block the constitutive Gli activity induced by loss of Suppressor of Fused (SUFU), a scaffolding protein that directly inhibits Gli function. Our studies reveal a family of bicyclic imidazolium derivatives that can inhibit Gli\u2010dependent transcription without affecting the ciliary trafficking or proteolytic processing of these transcription factors. We anticipate that these chemical antagonists will be valuable tools for investigating the mechanisms of Gli regulation and developing new strategies for targeting Gli\u2010driven cancers.<\/jats:p>","DOI":"10.1002\/cmdc.202000169","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T15:14:21Z","timestamp":1586358861000},"page":"1044-1049","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Bicyclic Imidazolium Inhibitors of Gli Transcription Factor Activity"],"prefix":"10.1002","volume":"15","author":[{"given":"Marisa E.","family":"Hom","sequence":"first","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison E.","family":"Ondrus","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"},{"name":"Present address: Division of Chemistry and Chemical Engineering California Institute of Technology  Pasadena CA 91125 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyo","family":"Sakata\u2010Kato","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"},{"name":"Present address: Global Health Drug Discovery Institute  Beijing 100192 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Rack","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"},{"name":"Present address: Thermo Fisher Scientific  Carlsbad CA 92008 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-8436","authenticated-orcid":false,"given":"James K.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"},{"name":"Department of Developmental Biology Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"},{"name":"Department of Chemistry Stanford University  269 Campus Dr., CCSR 3155 Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"e_1_2_2_1_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.21.4393"},{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/287795a0"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/332371a0"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.10.10.5408"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509927103"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.166892"},{"key":"e_1_2_2_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.052126"},{"key":"e_1_2_2_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1902910"},{"key":"e_1_2_2_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205748"},{"key":"e_1_2_2_10_1","first-page":"10","volume":"6","author":"Cohen M.","year":"2015","journal-title":"Nat. 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