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Background and Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease with limited treatment options. Drug repurposing offers a promising strategy to find effective treatments.

Experimental Approach: We identified birinapant, bardoxolone methyl and salicylic acid as repurposing candidates for ADPKD and applied thermal proteome profiling to identify disease-relevant targets.

Key Results: Our results uncovered shared effects between the three drugs, including a thermal shift in ADP/ATP translocases (SLC25A4/5/6) caused by reduced ATP production. As expected, salicylic acid displayed a polypharmacological profile but also engaged enzymes along the N-linked glycosylation pathway and inhibited PTK2 (FAK), an activator of the proliferative PI3K/Akt/mTOR pathway. Orthogonal assays and computational modelling confirmed these findings and located the binding site (499–504) of salicylic acid within PTK2's ATP-binding pocket. Engagement of several targets was achieved at clinically relevant concentrations.

Conclusions and Implications: We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action.