Premium
Identification and characterization of novel small‐molecule inhibitors of SLC26A3
Author(s) -
Park Jinhong,
Namkung Wan
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.824.5
Subject(s) - bicarbonate , chemistry , small molecule , microbiology and biotechnology , biochemistry , biology , organic chemistry
SLC26A3 (downregulated in adenoma, DRA), an anion exchanger, is highly expressed in the luminal membrane of intestinal epithelial cells, and loss‐of‐function mutations in this gene result in congenital chloride diarrhea caused by detect of chloride absorption and bicarbonate secretion in the intestine. Here, we report development of the selective small‐molecule inhibitors of DRA for the investigation of the effect of DRA inhibition on constipation and metabolic acidosis. A screen of ~3,000 compounds using a cell‐based high‐throughput screening (HTS) assay revealed four novel compounds of DRA inhibitors that fully blocked Cl − /I − exchange activity of DRA with IC 50 < 10 μM. The hit compounds strongly inhibited both Cl − /I − and Cl − /HCO 3− exchange activity of DRA. The most potent inhibitor significantly blocked Cl − /I − exchange activity of DRA (IC 50 of ~3 μM) but it did not affect the activity of SLC26A4 (pendrin), SLC26A7, SLC26A9, CFTR and ANO1. The small‐molecule DRA inhibitors identified here may be useful tools for pharmacological dissection of DRA and drug discovery for treating constipation and metabolic acidosis. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .