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

Limin Su1, Haoxing Yuan1, Haoran Zhang1

  • 1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, China.

FEBS Open Bio
|June 24, 2022
PubMed

Insights

PF-06409577, an AMPK activator, shows therapeutic potential for autosomal dominant polycystic kidney disease (ADPKD). It effectively reduced cyst cell proliferation and fluid secretion in ADPKD models, offering a more potent alternative to metformin.

Area of Science:

  • Nephrology
  • Pharmacology
  • Genetics

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst development and expansion due to epithelial cell over-proliferation and excessive fluid secretion.
  • Metformin shows limited potency in inhibiting renal cyst growth in ADPKD mouse models, highlighting the need for more effective adenosine monophosphate-activated protein kinase (AMPK) activators.

Purpose of the Study:

  • To evaluate the therapeutic potential of PF-06409577, an AMPK activator, for treating autosomal dominant polycystic kidney disease (ADPKD) through a drug repurposing strategy.

Main Methods:

  • Utilized cellular, ex vivo, and in vivo models of ADPKD to assess the efficacy of PF-06409577.
  • Investigated the drug's impact on mammalian target of rapamycin (mTOR) pathway-mediated cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR)-regulated fluid secretion.

Main Results:

  • PF-06409577 significantly down-regulated mTOR-mediated proliferation of cyst-lining epithelial cells in ADPKD models.
  • PF-06409577 effectively reduced cystic fibrosis transmembrane conductance regulator-regulated cystic fluid secretion.
  • Demonstrated higher potency compared to metformin in inhibiting renal cyst growth.

Conclusions:

  • PF-06409577 exhibits significant therapeutic potential for treating autosomal dominant polycystic kidney disease (ADPKD).
  • The drug's ability to inhibit cell proliferation and fluid secretion makes it a promising candidate for ADPKD treatment.
Keywords:
ADPKDAMPKCFTRPF-06409577kidney diseasemTOR

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