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While inhibiting dysregulated PANX1 has been proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy, or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, hit\u2010to\u2010lead optimization is performed and a naphthyridone, compound\n                    <jats:bold>12<\/jats:bold>\n                    , is identified as a new PANX1 inhibitor with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 0.73\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    that does not affect pannexin\u2010homologous LRRC8\/SWELL1 channels. Using structure\u2013activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, it is revealed that compound\n                    <jats:bold>12<\/jats:bold>\n                    directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, it is found that compound\n                    <jats:bold>12<\/jats:bold>\n                    markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof\u2010of\u2010concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, uncover the binding site for future drug design, and present a targeted strategy for treating IBD.\n                  <\/jats:p>","DOI":"10.1002\/advs.202411538","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T05:34:43Z","timestamp":1735536883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Naphthyridones Targeting Pannexin 1 for Colitis Management"],"prefix":"10.1002","volume":"12","author":[{"given":"Wen\u2010Yun","family":"Hsueh","sequence":"first","affiliation":[{"name":"Department of Chemistry National Tsing Hua University  Hsinchu 300044 Taiwan"},{"name":"Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes  Miaoli County 350401 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