Potent and selective inhibition of anion exchange activity of SLC26A9 by A9-301.

SLC26A9 (solute carrier family 26, member 9) is highly expressed epithelial cells of the respiratory tract, stomach, pancreas and kidney, and acts as a Cl /HCO exchanger. SLC26A9 plays a pivotal role in HCO secretion in lung, and emerging evidence suggests that SLC26A9 is a therapeutic target for cystic fibrosis (CF) and potentially other mucosal obstructive pulmonary diseases. In this study, a cell-based high-throughput screening (HTS) assay was established and performed to identify highly potent and selective small molecule inhibitors of SLC26A9. Screening of 30,000 synthetic small molecules identified three novel SLC26A9 inhibitors. Unlike the previous non-selective SLC26A9 inhibitors, the novel SLC26A9 inhibitors potently and selectively inhibited anion exchange activity of SLC26A9. The most potent inhibitor, A9-301, significantly blocked Cl /I exchange activity of SLC26A9 (IC of ~100 nM) without affecting other anion exchanges and chloride channels, including SLC26A3 (DRA), SLC26A4 (pendrin), SLC26A7, CFTR and ANO1. These results suggest that the novel potent and selective inhibitors of SLC26A9 are useful tools for pharmacological dissection of SLC26A9 and may be potential therapeutic candidates for airway inflammatory diseases.