In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

Autor: Lin BL; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Matera D; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Doerner JF; Hydra Biosciences, Cambridge, MA 02138., Zheng N; Hydra Biosciences, Cambridge, MA 02138., Del Camino D; Hydra Biosciences, Cambridge, MA 02138., Mishra S; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Bian H; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Zeveleva S; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Zhen X; Hydra Biosciences, Cambridge, MA 02138., Blair NT; Hydra Biosciences, Cambridge, MA 02138., Chong JA; Hydra Biosciences, Cambridge, MA 02138., Hessler DP; Hydra Biosciences, Cambridge, MA 02138., Bedja D; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Zhu G; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Muller GK; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Ranek MJ; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205., Pantages L; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., McFarland M; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Netherton MR; Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Berry A; Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Wong D; Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Rast G; Drug Discovery Sciences, Boehringer Ingelheim GmbH & Co. KG, 88397 Biberach an der Riss, Germany., Qian HS; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Weldon SM; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Kuo JJ; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Sauer A; Drug Discovery Sciences, Boehringer Ingelheim GmbH & Co. KG, 88397 Biberach an der Riss, Germany., Sarko C; Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877., Moran MM; Hydra Biosciences, Cambridge, MA 02138., Kass DA; Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; dkass@jhmi.edu steven.pullen@boehringer-ingelheim.com., Pullen SS; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877; dkass@jhmi.edu steven.pullen@boehringer-ingelheim.com.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 May 14; Vol. 116 (20), pp. 10156-10161. Date of Electronic Publication: 2019 Apr 26.
DOI: 10.1073/pnas.1815354116
Abstrakt: Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models. Here, we report an orally bioavailable TRPC6 antagonist (BI 749327; IC 50 13 nM against mouse TRPC6, t 1/2 8.5-13.5 hours) with 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis.
Competing Interests: Conflict of interest statement: D.M., J.F.D., L.P., D.W., G.R., S.M.W., S.Z., H.S.Q, J.J.K, A.S., and S.S.P. are full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. M.M, M.R.N, A.B., and C.S. were full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. A.B. and M.R.N. are listed as coinventors on a US provisional patent application filed by Boehringer Ingelheim Pharmaceuticals, Inc. relevant to this work. J.F.D., N.Z., D.d.C., X.Z., N.T.B., J.A.C., D.P.H., and M.M.M. were employees of Hydra Biosciences, and received options. This work was supported in part by Boehringer Ingelheim Pharmaceuticals, Inc.
Databáze: MEDLINE
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