BI 749327 / Boehringer Ingelheim - LARVOL DELTA

TRPC6-mediated calcium signaling is involved in T2DM-induced hepatic steatosis and fibrosis and the modulation of ginsenoside Rg1. (PubMed, J Pharmacol Sci) - "In vitro, Rg1 and BI-749327 attenuated HG + PA-induced calcium overload, lipid accumulation, inflammation, mitochondrial dysfunction, and fibrotic activation, which were significantly abrogated by OAG. Our findings identify Rg1 as a promising agent for T2DM-associated hepatic complications via inhibiting TRPC6-mediated calcium signaling, highlighting TRPC6 as a novel therapeutic target."

Journal • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • NLRP3 • TRPC6 • TXNIP

PM2.5 toxin benzo[a]pyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling. (PubMed, bioRxiv) - "We found that both PM2.5 and B[a]P: (i) irreversibly activated of β2AR signaling via G i to PI3K/AKT; (ii) increased NFκB-activated release of proinflammatory cytokines through IKKαβ activation by PI3K/AKT, which was suppressed by the PI3K inhibitor LY 294002 (iii) desensitized and destroyed the activated β2AR receptor by endocytic recycling; (iv) also destroyed β2AR's signalplex partner CFTR by the same process; (v) activated the CFTR-bound calcium channel protein TRPC6 due to loss of inhibitory CFTR; leading to (vi) increased cytosolic [Ca 2+ ] concentration; (vii) increased ROS due to mitochondrial uncoupling; and (viii) increased expression of oxidative stress. Treatment with the TRPC6 inhibitor BI 749327 blocked steps (vi-viii), and preserved CFTR from endocytic loss...PM2.5 and the PM2.5 toxin benzo[a]pyrene (B[a]P) induce inflammation and oxidative stress in the airway by increased expression of TRPC6 and inactivation of β2AR/CFTR signaling. These discoveries..."

Journal • Alzheimer's Disease • Autism Spectrum Disorder • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Genetic Disorders • Inflammation • Movement Disorders • Parkinson's Disease • IL6 • MIR26A1 • MIR30B • MIR766 • TRPC6

TRPC6-TXNIP-NLRP3 signaling axis is involved in type 2 diabetes-associated cognitive dysfunction and the intervention of ginsenoside Rg1. (PubMed, Exp Neurol) - "In vitro experiments showed that the TRPC6 inhibitor BI749327 can effectively inhibit TRPC6-TXNIP activation, inhibit NLRP3 inflammasome assembly, and reduce neuronal damage and apoptosis, while maintaining intracellular Ca2+ homeostasis and mitochondrial membrane potential. In conclusion, TRPC6-induced calcium overload and the TXNIP-NLRP3 signaling pathway are involved in the development of TDACD. Moreover, the neuroprotective effects of Rg1 against TDACD are associated with inhibition of the TRPC6-TXNIP-NLRP3 signaling axis."

Journal • Cognitive Disorders • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • CASP3 • NLRP3 • TRPC6 • TXNIP

Transient receptor potential canonical 6 is critical for chronic lipopolysaccharide exposure-induced pulmonary injury and fibrosis. (PubMed, Toxicon) - "Notably, pharmacological inhibition of TRPC6 with BI-749327 ameliorated these pathological processes, whereas TRPC6 activation via OAG exacerbated them...Collectively, our findings identify TRPC6 as a pivotal mediator in LPS-induced pulmonary fibrosis by disrupting calcium homeostasis and activating NLRP3 and AIM2 inflammasomes, eventually resulting in TGF-β1/Smad-driven fibrotic remodeling. Thus, targeting TRPC6 may represent a promising therapeutic approach for mitigating chronic inflammation-associated pulmonary fibrosis."

Journal • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Pneumonia • Pulmonary Disease • Respiratory Diseases • IL1B • IL6 • NLRP3 • TGFB1 • TRPC6

BI-749327 inhibits the proliferation of hepatocellular carcinoma by targeting the TRPC6 channel. (PubMed, Eur J Pharmacol) - "BI-749327 directly binds TRPC6, inhibiting its channel activity and expression, thereby reducing [Ca2+]i and downstream Ca2+-related PI3K/AKT/mTOR signaling to suppress HCC progression. This study elucidates the BI-749327-TRPC6 interaction, provides a molecular basis for developing novel anti-HCC drugs, and establishes a research paradigm for other TRPC6 inhibitors."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • TRPC6

PGE2 signaling triggers CD31-independent transendothelial migration in vitro and in vivo. (PubMed, Am J Pathol) - "This pro-transmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 (TRPC6) antagonist, BI-749327...In vivo, PGE2 overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 pecam1-/- mice. The findings support earlier data that identified PGE2 as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate TRPC6."

Journal • Preclinical • Dermatitis • Dermatology • Immunology • CD31 • PECAM1 • PTGS1 • TRPC6

Deficiency of Endothelial TRPV4 Cation Channels Ameliorates Experimental Abdominal Aortic Aneurysm. (PubMed, Eur J Pharmacol) - "Our data underscore the pathogenic importance of Ca2+ perturbation in AAA and illuminate that endothelial TRPV4 cation channel could be harnessed for AAA treatment."

Journal • Cardiovascular • ELANE • TRPC1 • TRPC3 • TRPC6

TRPC6 A404V is a gain-of-function variant associated with doxorubicin-induced cardiotoxicity in patients (AHA 2024) - "The OAG effects were abolished by superfusion with 1 μM BI-749327 (a specific TRPC6 inhibitor). TRPC6 A404V is a gain-of-function variant with a higher binding affinity to OAG. Treatment with DOX but not DOXol greatly enhances TRPC6 WT and A404V channel activation by OAG. Thus, cancer patients carrying the TRPC6 A404V variant may be more vulnerable to develop HF upon treatment with anthracycline."

Clinical • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Heart Failure • Oncology • TRPC6

Inhibition and potentiation of the exercise pressor reflex by pharmacological modulation of TRPC6 in male rats. (PubMed, J Physiol) - "The exercise pressor reflex was evoked by statically contracting the triceps surae muscles before and after injection of the TRPC6 antagonist BI-749327 (n = 11; 12 μg kg-1 ) or SAR7334 (n = 11; 7 μg kg-1 ) or the TRPC6 positive modulator C20 (n = 11; 18 μg kg-1 )...In contrast, the positive modulator increased the pressor reflex to contraction and stretch, in addition to the sympathetic response to stretch. Our results provide strong support for a role played by the TRPC6 channel in evoking the mechanoreflex."

Journal • Preclinical • Reflex • PRPH • TRPC6

Cardiac TRPC6 N338S is a Gain-of-Function Mutation Associated With Doxorubicin-Induced Cardiomyopathy (AHA 2022) - "However, the TRPC6 N338S mutant has not been characterized, and how it affects cardiac function is unknown.Hypothesis: We hypothesized that TRPC6 N338S is a gain-of-function mutation producing intracellular Ca2+ overload in cardiomyocytes. Using patch clamp recording, molecular biological and molecular docking analyses, we assessed the function of TRPC6 N338S heterologously expressed in HL-1 cardiac cells. TRPC6 N338S significantly increased the current densities of TRPC6 (defined as 1 µM BI-749327 sensitive components, a highly selective TRPC6 inhibitor) in HL-1 cells at baseline and after exposure to 50 μM 1-oleoyl 2-acetyl-sn-glycerol (OAG, an activator of TRPC6), compared to cells expressing TRPC6 WT. TRPC6 N338S mutation strengthens the interaction with OAG, stabilizes the OAG-TRPC6 N338S complex, and enhances the OAG effects. Treatment with DOX significantly increases the expression and function of TRPC6 N338S in HL-1 cells. Hence, the TRPC6 N338S is a..."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • TRPC6

Interruption of TRPC6-NFATC1 signaling inhibits NADPH oxidase 4 and VSMCs phenotypic switch in intracranial aneurysm. (PubMed, Biomed Pharmacother) - "The VIVIT (NFATC1 inhibitor) and BI-749327 (TRPC6 inhibitor) treatment reduced the expressions of NOX4, p22phox and p47phox and the production of ROS, and significantly improved VSMCs phenotypic switch in IA rats and cells...Furthermore, the results also revealed that NFATC1 could regulate NOX4 transcription by binding to its promoter. Our findings reveal that interrupting the TRPC6-NFATC1 signaling inhibits NOX4 and improves VSMCs phenotypic switch in IA, and regulating Ca homeostasis may be an important therapeutic strategy for IA."

Journal • Cardiovascular • CNS Disorders • Vascular Neurology • NFATC1 • NOX4

Improvement of platelet preservation by inhibition of TRPC6. (PubMed, Transfus Med) - "Inhibition of TRPC6 improves the quality of PLT preservation by inhibiting the Ca signal mediated by TRPC6."

Journal • SELP

Pharmacological TRPC6 inhibition improves survival and muscle function in mice with duchenne muscular dystrophy. (PubMed, JCI Insight) - "Gene pathways reduced by BI 749327 treatment most prominently regulate fat metabolism and TGFβ1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy."

Journal • Preclinical • Cardiovascular • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Mechanosensitive Cation Currents Through TRPC6 and Piezo1 Channels in Human Pulmonary Arterial Endothelial Cells. (PubMed, Am J Physiol Cell Physiol) - "The membrane stretch-mediated cation currents and increase in [Ca] in human PAECs were significantly decreased by GsMTX4, a blocker of Piezo1 channels and by BI-749327, a selective blocker of TRPC6 channels...These data indicate that, while both TRPC6 and Piezo1 are involved in generating mechanosensitive cation currents and increases in [Ca] in human PAECs undergoing mechanical stimulation, only TRPC6 (but not Piezo1) is sensitive to the second messenger diacylglycerol. Selective blockers of these channels may help develop novel therapies for mechanotransduction-associated pulmonary vascular remodeling in patients with pulmonary arterial hypertension."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Klotho Modulates Pro-Fibrotic Activities in Human Atrial Fibroblasts through Inhibition of Phospholipase C Signaling and Suppression of Store-Operated Calcium Entry. (PubMed, Biomedicines) - "Klotho inhibited pro-fibrotic activities and SOCE by inhibiting the PLC signaling and suppressing the TRP currents, which may provide a novel insight into atrial fibrosis and arrhythmogenesis."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology

TRPC6 N338S is a gain-of-function mutant identified in patient with doxorubicin-induced cardiotoxicity. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "A 24-h pretreatment with 0.5 μM doxorubicin (DOX) further potentiated the effects of OAG on TRPC6 N338S current densities and [Ca], and these effects were abolished by 1 μM BI-749327, a highly selective TRPC6 inhibitor. However, the N338S mutation strengthened the interaction with OAG, therefore stabilizing the OAG-TRPC6 N338S complex and enhancing OAG binding affinity. Our results indicate that TRPC6 N338S is a gain-of-function mutant that may contribute to DOX-induced cardiotoxicity by increasing Ca influx and [Ca] in cardiomyocytes."

Journal • Breast Cancer • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology • Solid Tumor

Interaction of background Ca influx, sarcoplasmic reticulum threshold and heart failure in determining propensity for Ca waves in sheep heart. (PubMed, J Physiol) - "Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca . We investigate the mechanism by which raising external Ca causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca influx via the TRPC6 channel is responsible for SR Ca overload and Ca waves. The increased propensity for Ca waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca waves may arise in heart failure, providing a basis for future work and novel therapeutic targets."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure • TRPC1

Role of TRPC6 in kidney damage after acute ischemic kidney injury. (PubMed, Sci Rep) - "We used Trpc6 mice and pharmacological blockade (SH045 and BI-749327), to evaluate short-term AKI outcomes...Therefore, we conclude that TRPC6 does not play a role in the acute phase of AKI. Our results may have clinical implications for safety and health of humans with TRPC6 gene variations, with respect to mutated TRPC6 channels in the response of the kidney to acute ischemic stimuli."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease

TRPC6, a Therapeutic Target for Pulmonary Hypertension. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH."

Journal • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Blockade of TRPC6 Channels Attenuates Growth Factor-Mediated Activation of AKT/mTOR Signaling in Human Pulmonary Arterial Smooth Muscle Cells (ATS 2021) - "We sought to investigate whether blockade of receptor-operated Ca2+ channels with 2-aminophenyl borate (2-APB), a non-selective blocker of cation channels, and BI-749237, a selective blocker of TRPC6 channels, inhibits GF-mediated activation of AKT/mTOR signaling in human PASMC. Normal human PASMC were cultured in smooth muscle growth medium (GM) supplemented with 5% fetal bovine serum, 5 ng/ml human epidermal GF (hEGF), 5 ng/ml human fibroblast GF (hFGF), 5 µg/ml insulin, 50 μg/ml ascorbic acid, 10 mM L-glutamine, 30 mg/ml gentamicin and 15 μg/ml amphotericin B. Western blot were performed to measure expression of phosphorylated (p) AKT (pAKT), AKT, pmTOR and mTOR. The band intensity of pAKT, AKT, pmTOR and mTOR from cells treated with GM or PDGF-BB (10 ng/ml) in presence or absence of BAPTA (20 mM), BAPTA-AM (25 µM), 2-APB (50 µM) or BI-749327 (0.25 or 75 µM) was normalized to control and expressed in arbitrary units. Chelation of extracellular Ca2+..."

Hypertension • Pulmonary Arterial Hypertension • Respiratory Diseases