In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease.

Autor:	Booij TH; Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.; NEXUS Personalized Health Technologies, ETH Zürich, Switzerland., Leonhard WN; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Bange H; OcellO B.V., Leiden, The Netherlands., Yan K; OcellO B.V., Leiden, The Netherlands., Fokkelman M; Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands., Plugge AJ; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Veraar KAM; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Dauwerse JG; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands., van Westen GJP; Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden, The Netherlands., van de Water B; Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands., Price LS; Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.; OcellO B.V., Leiden, The Netherlands., Peters DJM; Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of molecular cell biology [J Mol Cell Biol] 2020 Aug 01; Vol. 12 (8), pp. 644-653.
DOI:	10.1093/jmcb/mjz029
Abstrakt:	Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function. (© The Author(s) 2019. Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)
Databáze:	MEDLINE
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