PT - JOURNAL ARTICLE AU - Elizabeth J. Wilk AU - Timothy C. Howton AU - Jennifer L. Fisher AU - Vishal H. Oza AU - Ryan T. Brownlee AU - Kasi C. McPherson AU - Hannah L. Cleary AU - Bradley K. Yoder AU - James F. George AU - Michal Mrug AU - Brittany N. Lasseigne TI - Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse model gene expression reversion AID - 10.1101/2022.12.02.518863 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.12.02.518863 4099 - http://biorxiv.org/content/early/2022/12/03/2022.12.02.518863.short 4100 - http://biorxiv.org/content/early/2022/12/03/2022.12.02.518863.full AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this approach, we prioritized 29 unique drug targets differentially expressed in ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD. Graphical abstract of the study.Competing Interest StatementM. M. reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals, Sanofi, Palladio Biosciences, Reata, Natera, Chinook Therapeutics, Goldilocks Therapeutics and Carraway Therapeutics.ADPKDAutosomal dominant polycystic kidney diseasePC1polycystin-1PC2polycystin-2LINCSLibrary of Integrated Network-Based Cellular SignaturescAMPcyclic adenosine monophosphateMOAmechanism of actionKOknock-outQCquality controlLFClog2 fold changeFEAFunctional Enrichment AnalysisGOGene OntologyGO:BPGO biological processGO:CCGO cellular componentGO:MFGO molecular functionGSEAgene set enrichment analysisWTCSweighted connectivity scoreESenrichment scoreNCSnormalized connectivity scoreDSEADrug Set Enrichment AnalysisNEKsNIMA KinasesRAASrenin-angiotensin-aldosteroneESRDend-stage renal diseaseAKIAcute kidney injuryCKDchronic kidney diseaseNSCLCnon-small cell lung cancerOCDobsessive compulsive disorderSNRIserotonin-norepinephrine reuptake inhibitorHMGCRhydroxymethylglutaryl-CoA reductaseCKD-aPchronic kidney disease-associated pruritusCaM-MLCKcalmodulin-dependent myosin light chain kinaseNF-κBnuclear factor kappa-light-chain-enhancer of activated B cellsPPARαperoxisome proliferator-activated receptor α