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Kidney Week

Abstract: FR-PO727

Computational Drug Screening Identifies the Androgen Receptor Antagonist Flutamide as a Potential Treatment Option for Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Perco, Paul, Medical University Innsbruck, Innsbruck, Austria
  • Leierer, Johannes, Medical University Innsbruck, Innsbruck, Austria
  • Rudnicki, Michael, Medical University Innsbruck, Innsbruck, Austria
  • Mayer, Gert J., Medical University Innsbruck, Innsbruck, Austria
Background

Treatment options for patients with autosomal dominant polycystic kidney disease (ADPKD) are limited and novel therapies are needed. A key hallmark of ADPKD is enhanced tubular epithelial cell proliferation.

Methods

We constructed a network-based molecular model of ADPKD using ADPKD-associated molecular features from scientific literature, the OMIM database, clinical trials on ADPKD, and a human ADPKD transcriptomics dataset. We computationally screened compound libraries with the ADPKD molecular model using data from the Connectivity Map and a constructed library of literature-based drug mechanism of action molecular models. We finally evaluated the impact of top-ranked compounds on cell viability and proliferation in two ADPKD cell lines and HK2 cells.

Results

Five compounds - flutamide, mifepristone, spironolactone, troglitazone, and vorinostat - were identified in the computational drug screen being capable of inversing the ADPKD gene signature and showing significant positive overlap with the ADPKD molecular model. Four compounds had a significant negative impact on cell viability in ADPKD cell lines as compared to treated HK2 cells. Flutamide had the strongest impact on ADPKD cell viability (65.4% in WT9-7, 67.8% in WT9-12, 92.0% in HK2 cells). Flutamide on top significantly reduced cell proliferation in ADPKD cells (41.1% in WT9-7 and 41.9% in WT9-12) as compared to HK2 cells (92.8%).

Conclusion

Flutamide significantly hampers cell viability and cell proliferation of ADPKD cells and warrants follow-up studies to investigate its potential as novel treatment option for patients with ADPKD.

The impact of flutamide on cell viability and cell proliferation in the two ADPKD cell lines WT9-7 and WT9-12 as well as in control human renal proximal tubular (HK2) cells is displayed. Data are presented as mean and standard deviation

Funding

  • Government Support - Non-U.S.