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Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish<jats:italic>pkd2<\/jats:italic>mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human<jats:italic>PKD1<\/jats:italic>cystic cells. Amongst these were an androgen, 5\u03b1\u2212androstane 3,17-dione, detected as the strongest enhancer of the<jats:italic>pkd2<\/jats:italic>phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the<jats:italic>pkd2<\/jats:italic>tail phenotype and<jats:italic>in vitro<\/jats:italic>cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.<\/jats:p>","DOI":"10.1038\/s41598-019-56995-7","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T11:02:26Z","timestamp":1578567746000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2\u2212\/\u2212 phenotype"],"prefix":"10.1038","volume":"10","author":[{"given":"A.","family":"Metzner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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