ArticleJCI insight2018
SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 54 citations in OpenAlex.
- Epithelial Chloride and Bicarbonate Transport in Intestinal Barrier Failure: A Molecular Target-Validation Assessment of CFTR and SLC26A3/DRA in Inflammatory Bowel Disease.International journal of molecular sciences · 2026Review
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- CFD protein deficiency induce slow transit constipation is correlated with gut microbial dysbiosis.Scientific reports · 2026Article
- Article
- Innate immune sensing of rotavirus by intestinal epithelial cells leads to diarrhea.Cell host & microbe · 2025Article
- DRA involvement in linaclotide-stimulated bicarbonate secretion during loss of CFTR function.JCI insight · 2024Article
- Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria.RSC medicinal chemistry · 2024Article
- Congenital chloride diarrhoea in a Chinese infant with a compound heterozygous SLC26A3 mutation.BMC pediatrics · 2024Article
- Key role of down-regulated in adenoma (bioRxiv : the preprint server for biology · 2024Article
- Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.RSC medicinal chemistry · 2023Article
- A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.Gastroenterology · 2023Article
- SLC26A3 (DRA) is stimulated in a synergistic, intracellular CaAmerican journal of physiology. Cell physiology · 2023Article
- Small molecule inhibitors of intestinal epithelial anion exchanger SLC26A3 (DRA) with a luminal, extracellular site of action.European journal of medicinal chemistry · 2023Article
- Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis.JCI insight · 2022Article
- Lubiprostone is non-selective activator of cAMP-gated ion channels and Clc-2 has a minor role in its prosecretory effect in intestinal epithelial cells.Molecular pharmacology · 2022Article
- mOrange2, a Genetically Encoded, pH Sensitive Fluorescent Protein, is an Alternative to BCECF-AM to Measure Intracellular pH to Determine NHE3 and DRA Activity.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2022Article
- Construction of a novel choline metabolism-related signature to predict prognosis, immune landscape, and chemotherapy response in colon adenocarcinoma.Frontiers in immunology · 2022Article
- Chloride transport modulators as drug candidates.American journal of physiology. Cell physiology · 2021Review
- SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine.JCI insight · 2021Article
- Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas.JCI insight · 2021Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
SLC26A3 (downregulated in adenoma; DRA) is a Cl-/anion exchanger expressed in the luminal membrane of intestinal epithelial cells, where it facilitates electroneutral NaCl absorption. SLC26A3 loss of function in humans or mice causes chloride-losing diarrhea. Here, we identified slc26a3 inhibitors in a screen of 50,000 synthetic small molecules done in Fischer rat thyroid (FRT) cells coexpressing slc26a3 and a genetically encoded halide sensor. Structure-activity relationship studies were done on the most potent inhibitor classes identified in the screen: 4,8-dimethylcoumarins and acetamide-thioimidazoles. The dimethylcoumarin DRAinh-A250 fully and reversibly inhibited slc26a3-mediated Cl- exchange with HCO3-, I-, and thiocyanate (SCN-), with an IC50 of ~0.2 μM. DRAinh-A250 did not inhibit the homologous anion exchangers slc26a4 (pendrin) or slc26a6 (PAT-1), nor did it alter activity of other related proteins or intestinal ion channels. In mice, intraluminal DRAinh-A250 blocked fluid absorption in closed colonic loops but not in jejunal loops, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum. Oral DRAinh-A250 and tenapanor comparably reduced signs of constipation in loperamide-treated mice, with additive effects found on coadministration. DRAinh-A250 was also effective in loperamide-treated cystic fibrosis mice. These studies support a major role of slc26a3 in colonic fluid absorption and suggest the therapeutic utility of SLC26A3 inhibition in constipation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.