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In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease
Tijmen H. Booij1,2,† , Wouter N. Leonhard3,† , Hester Bange4 , Kuan Yan4 , Michiel Fokkelman1 , Anna J. Plugge3 , Kimberley A.M. Veraar3 , Johannes G. Dauwerse3 , Gerard J.P. van Westen5 , Bob van de Water1 , Leo S. Price1,4,† , Dorien J.M. Peters3,†,*
1Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
2Present address: NEXUS Personalized Health Technologies, ETH Zürich, Switzerland
3Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands
4OcellO B.V., Leiden, The Netherlands
5Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden, The Netherlands
These authors contributed equally to this work
*Correspondence to:Dorien J.M. Peters ,
J Mol Cell Biol, Volume 12, Issue 8, August 2020, Pages 644-653
Keyword: PKD, celastrol, pyrvinium pamoate, high-content screening, 3D Topic: phenotypesignal transductionrenal functioncystsdrug screeningpolycystic kidney diseasesmicerenal cysttriterpenoid compoundmolecule

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.