A deepening understanding of the relationship between transient receptor potential canonical channel 5 (TRPC5) and chronic kidney disease (CKD), has led to the emergence of several types of TRPC5 inhibitors displaying clear therapeutic effect. Herein, we report the synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors, culminating in the discovery of compound 16g with subtype selectivity. Compared with GFB-8438, a potent TRPC5 inhibitor (Goldfinch Bio), compound 16g showed improved inhibition of TRPC5 and enhanced protective effect against protamine sulfates (PS)-induced podocyte injury in vitro. In addition, compound 16g did not induce cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, indicating its utility as a potent and safe inhibitor for studying the function of TRPC5.

01 Feb 2022·Journal of Biological ChemistryQ2 · BIOLOGY

Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903

Q2 · BIOLOGY

Article

Author: Hosseini-Farahabadi, Sara ; Linley, Deborah M ; Bauer, Claudia C ; Balgi, Aruna D ; Roberge, Michel ; Choi, Kunho ; Pickles, Isabelle B ; Beech, David J ; Baradaran-Heravi, Alireza ; Bon, Robin S

Nonsense mutations, which occur in ∼11% of patients with genetic disorders, introduce premature termination codons (PTCs) that lead to truncated proteins and promote nonsense-mediated mRNA decay. Aminoglycosides such as G418 permit PTC readthrough and so may be used to address this problem. However, their effects are variable between patients, making clinical use of aminoglycosides challenging. In this study, we tested whether TRPC nonselective cation channels contribute to the variable PTC readthrough effect of aminoglycosides by controlling their cellular uptake. Indeed, a recently reported selective TRPC5 inhibitor, AC1903, consistently suppressed G418 uptake and G418-induced PTC readthrough in the DMS-114 cancer cell line and junctional epidermolysis bullosa (JEB) patient-derived keratinocytes. Interestingly, the effect of AC1903 in DMS-114 cells was mimicked by nonselective TRPC inhibitors, but not by well-characterized inhibitors of TRPC1/4/5 (Pico145, GFB-8438) or TRPC3/6/7 (SAR7334), suggesting that AC1903 may work through additional or undefined targets. Indeed, in our experiments, AC1903 inhibited multiple TRPC channels including TRPC3, TRPC4, TRPC5, TRPC6, TRPC4-C1, and TRPC5-C1, as well as endogenous TRPC1:C4 channels in A498 renal cancer cells, all with low micromolar IC₅₀ values (1.8-18 μM). We also show that AC1903 inhibited TRPV4 channels, but had weak or no effects on TRPV1 and no effect on the nonselective cation channel PIEZO1. Our study reveals that AC1903 has previously unrecognized targets, which need to be considered when interpreting results from experiments with this compound. In addition, our data strengthen the hypothesis that nonselective calcium channels are involved in aminoglycoside uptake.

14 Nov 2019·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model

Q3 · MEDICINE

Article

Author: Mundel, Peter ; Ledeboer, Mark W ; Westerling-Bui, Amy ; Beconi, Maria ; Daniels, Matthew ; Coeffet-Le Gal, Marie ; Yu, Maolin ; Reilly, John F ; Malojcic, Goran ; Tibbitts, Thomas T ; Pan-Zhou, Xin-Ru ; Harmange, Jean-Christophe

The nonselective Ca²⁺-permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca²⁺ signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases. Herein, we describe the identification of a novel TRPC5 inhibitor, GFB-8438, by systematic optimization of a high-throughput screening hit, pyridazinone 1. GFB-8438 protects mouse podocytes from injury induced by protamine sulfate (PS) in vitro. It is also efficacious in a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of FSGS, significantly reducing both total protein and albumin concentrations in urine.

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Indication	Highest Phase	Country/Location	Organization	Date
Glomerulosclerosis, Focal Segmental	Discovery	US	Goldfinch Bio, Inc.Startup	-

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