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• W2999791864 abstract "Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2 . 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 pkd2 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 PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 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 pkd2 tail phenotype and in vitro 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." @default.
• W2999791864 created "2020-01-23" @default.
• W2999791864 creator A5009706482 @default.
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• W2999791864 date "2020-01-09" @default.
• W2999791864 modified "2023-10-01" @default.
• W2999791864 title "A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2−/− phenotype" @default.
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• W2999791864 doi "https://doi.org/10.1038/s41598-019-56995-7" @default.
• W2999791864 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6952374" @default.
• W2999791864 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31919453" @default.
• W2999791864 hasPublicationYear "2020" @default.
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