Kidney Week

Abstract: SA-PO317

Small Molecule Inhibition of TRPC5 Protects Against Podocyte Injury and Proteinuria in FSGS

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Westerling-Bui, Amy Duyen, Goldfinch Bio, Cambridge, Massachusetts, United States

Amy Duyen Westerling-Bui,

• Beconi, Maria, Goldfinch Bio, Cambridge, Massachusetts, United States

Maria Beconi,

• Hoang, Hien G., Goldfinch Bio, Cambridge, Massachusetts, United States

Hien G. Hoang,

• Yu, Maolin, Goldfinch Bio, Cambridge, Massachusetts, United States

Maolin Yu,

• Daniels, Matthew, Goldfinch Bio, Cambridge, Massachusetts, United States

Matthew Daniels,

• Malojcic, Goran, Goldfinch Bio, Cambridge, Massachusetts, United States

Goran Malojcic,

• Ledeboer, Mark, Goldfinch Bio, Cambridge, Massachusetts, United States

Mark Ledeboer,

• Walsh, Liron, Goldfinch Bio, Cambridge, Massachusetts, United States

Liron Walsh,

• Tibbitts, Thomas T., Goldfinch Bio, Cambridge, Massachusetts, United States

Thomas T. Tibbitts,

• Harmange, Jean-Christophe P., Goldfinch Bio, Cambridge, Massachusetts, United States

Jean-Christophe P. Harmange,

• Mundel, Peter H., Goldfinch Bio, Cambridge, Massachusetts, United States

Peter H. Mundel,

Background

FSGS is a rare kidney disorder of the podocyte with a high likelihood of progression to kidney failure. The activation of the TRPC5-RAC1 pathway in podocytes is a critical driver of proteinuria in many forms of familial and sporadic FSGS. The Ca²⁺permeable TRPC5 channel is a critical mediator of proteinuria in FSGS. Inhibition of TRPC5 channel activity protects against proteinuria and podocyte loss in AT1R transgenic and Dahl salt sensitive rats (Zhou et al. Science, 2017).

Methods

We performed high throughput screening of a structurally diverse compound collection followed by lead optimization for the development of several potent TRPC5 inhibitors. We then analyzed the TRPC5 inhibitors in several in vitro models of podocyte injury (protamine sulfate induced cytoskeletal disruption, restoration of stress fibers in synaptopodin-depleted podocytes, inhibition of pathogenic podocyte migration) and in the DOCA-salt rat model of FSGS in vivo.

Results

Here we report the identification of potent and selective small molecule inhibitors of TRPC5. activity against TRPC5 and selectivity across other TRP channels were determined using FLIPR based assays and electrophysiology. We show that TRPC5 inhibition protects against protamine sulfate induced loss of stress fibers. TRPC5 inhibition also restores stress fibers in podocytes after knockdown of synaptopodin. We further show that inhibition of TRPC5 suppresses pathogenic podocyte motility in a scratch assay. Finally, we demonstrate that inhibition of TRPC5 suppresses proteinuria in hypertension-induced FSGS in uninephrectomized DOCA salt rats without altering blood pressure.

Conclusion

In summary, we have identified new selective small molecule inhibitors of TRPC5 for the treatment of proteinuria in FSGS.

Funding

• Commercial Support – Goldfinch Bio, Inc.