PF‐06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over‐proliferation of cyst‐lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate‐activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF‐06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF‐06409577 effectively down‐regulated mammalian target of rapamycin pathway‐mediated proliferation of cyst‐lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator‐regulated cystic fluid secretion. Overall, our data suggest that PF‐06409577 holds therapeutic potential for ADPKD treatment. Over‐proliferation of cyst‐lining epithelial cells and excessive cystic fluid secretion are the most important causes of renal cyst enlargement. In this study, we evaluated the therapeutic benefits of PF‐06409577, an AMPK activator, in ADPKD. PF‐06409577 effectively down‐regulated mTOR pathway‐mediated proliferation of cyst‐lining epithelial cells and CFTR‐regulated cystic fluid secretion, delaying the progression of ADPKD significantly. PF‐06409577 holds therapeutic potential for ADPKD.