Abstract: FR-PO127
A Novel, Selective TRPC6 Antagonist Reduces Renal Interstitial Fibrosis in the Mouse Unilateral Ureteral Obstruction Model
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Pullen, Steven S., Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
- Matera, Damian C., Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
- Del camino, Donato, Rheostat Therapeutics Inc., Brookline, Massachusetts, United States
- Zheng, Nan, Hydra Biosciences, Belmont, Massachusetts, United States
- Doerner, Julia, Hydra Biosciences, Belmont, Massachusetts, United States
- Bian, Hong, Boehringer Ingelheim, Ridgefield, Connecticut, United States
- Chen, Hongxing, Boehringer Ingelheim, Ridgefield, Connecticut, United States
- Blair, Nathaniel T., Hydra Biosciences, Belmont, Massachusetts, United States
- Chong, Jayhong A., Hydra Biosciences, Belmont, Massachusetts, United States
- Hessler, David P., Hydra Biosciences, Belmont, Massachusetts, United States
- Netherton, Matthew R., Foghorn Therapeutics, Cambridge, Massachusetts, United States
- Wong, Diane, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
- Weldon, Steven M., Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
- Kuo, Jay J., Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
- Sauer, Achim, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
- Sarko, Christopher R., Novartis Institutes for Biomedical Research, San Ramon, California, United States
- Moran, Magdalene M., Hydra Biosciences, Belmont, Massachusetts, United States
Background
A role for dysregulation of the non-selective cation channel TRPC6 in the development of FSGS is well-established based on the identification of multiple gain-of-function mutations in humans which cause disease by cytoskeletal alterations in podocytes, leading to impairment of the glomerular filtration barrier. Despite the strong evidence linking elevated TRPC6 activity to CKD, no inhibitors have advanced to clinical testing due to challenges associated with achieving selectivity against related ion channels and identifying compounds with a suitable pharmacokinetic profile for oral dosing.
Methods
A novel TRPC6 antagonist, BI 749327, was characterized with in vitro electrophysiology measurements using HEK293 cell transfectants and in vivo in the mouse unilateral ureteral obstruction (UUO) model of renal fibrosis.
Results
BI 749327 has a manual patch-clamp IC50 value of 13 nM against TRPC6 and 85- and 42-fold selectivity against TRPC3 and TRPC7, respectively. Oral gavage dosing with BI 749327 produced plasma exposures predicted to provide potent 24 hour inhibition. Treatment of mice undergoing UUO surgery with BI 749327 inhibited the development of fibrosis as measured by hydroxyproline incorporation. TRPC6 dependent inhibition was confirmed as mice lacking TRPC6 had a similar reduction in fibrosis in the UUO model when compared with BI 749327 treated wild-type mice and by the demonstration that the compound had no further effect on fibrosis development in this model when administered to TRPC6 deficient mice.
Conclusion
The opportunity for treatment with a TRPC6 antagonist to inhibit renal fibrosis in addition to restoring podocyte calcium homeostasis further highlights the therapeutic potential of this mechanism for the treatment of CKD. These results are the first demonstration of in vivo benefit in a disease model with TRPC6 pharmacological inhibition, and BI 749327 provides a tool for further evaluating TRPC6 inhibition for the treatment of CKD.
Funding
- Commercial Support –