BACKGROUND Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Tolvaptan, the only drug approved for ADPKD treatment, results in serious side-effects, warranting the need for novel drugs. METHODS In this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. We followed an integrative computational approach using a combination of gene expression profiling, bioinformatics and cheminformatics data. FINDINGS We identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinically-approved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone. Further testing the efficacy of six candidate drugs for inhibition of cyst swelling using a human 3D-cyst assay, revealed that three of the six had cyst-growth reducing effects with limited toxicity. INTERPRETATION Our data further establishes drug repurposing as a robust drug discovery method, with three promising drug candidates identified for ADPKD treatment (Meclofenamic Acid, Gamolenic Acid and Birinapant). Our strategy that combines multiple-omics data, can be extended for ADPKD and other diseases in the future. FUNDING European Union's Seventh Framework Program, Dutch Technology Foundation Stichting Technische Wetenschappen and the Dutch Kidney Foundation.

中文翻译：

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从疾病阶段的特定基因表达谱对新型ADPKD候选药物进行优先排序。

背景技术常染色体显性多囊肾病（ADPKD）是由PKD1或PKD2基因突变引起的终末期肾衰竭的最常见原因之一。托伐普坦（Tolvaptan）是唯一批准用于ADPKD治疗的药物，会产生严重的副作用，因此需要新药。方法在本研究中，我们对处于不同疾病阶段的Pkd1cko小鼠进行了RNA测序，并在有/无药物治疗的情况下确定了与ADPKD进展有关的基因，这些基因进一步被用于确定ADPKD的新型候选药物。我们遵循综合计算方法，结合了基因表达谱，生物信息学和化学信息学数据。结果我们鉴定了1162个基因，这些基因在临床前模型中被证明有效的药物治疗了小鼠后具有正常的表达。这些基因与临床批准的ChEMBL药物的靶标亲和力特征相交，导致鉴定出116种靶向29种蛋白质的药物，其中有几种以前与多囊肾疾病有关，例如罗格列酮。使用人3D囊肿试验进一步测试了六种候选药物抑制囊肿的功效，发现六种候选药物中的三种具有减少囊肿生长的作用，且毒性有限。解释我们的数据进一步确定了将药物重新利用作为一种可靠的药物发现方法，并确定了三种有望用于ADPKD治疗的候选药物（甲氯芬那酸，甘汞烯酸和Birinapant）。结合多组学数据的我们的策略将来可以扩展到ADPKD和其他疾病。资助欧盟第七框架计划，