國家衛生研究院 NHRI:Item 3990099045/16710

NHRI > Institute of Biotechnology and Pharmaceutical Research > Jinq-Chyi Lee > Periodical Articles > Item 3990099045/16710

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/16710

Title:	Novel naphthyridones targeting pannexin 1 for colitis management
Authors:	Hsueh, WY;Wu, YL;Weng, MT;Liu, SY;Santavanond, JP;Liu, YC;Lin, C;Lai, CN;Lu, YR;Hsu, JY;Gao, HY;Lee, JC;Wei, SC;Lyu, PC;Poon, IKH;Hsieh, HP;Chiu, YH
Contributors:	Institute of Biotechnology and Pharmaceutical Research;Institute of Population Health Sciences
Abstract:	Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. 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-to-lead optimization is performed and a naphthyridone, compound 12, is identified as a new PANX1 inhibitor with an IC50 of 0.73 mu m that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, it is revealed that compound 12 directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, it is found that compound 12 markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept 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.
Date:	2024-12-30
Relation:	Advanced Science. 2024 Dec 30;Article in Press.
Link to:	http://dx.doi.org/10.1002/advs.202411538
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2198-3844&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:001388330600001
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85213705839
Appears in Collections:	[Jinq-Chyi Lee] Periodical Articles [Hsing-Pang Hsieh] Periodical Articles [Others] Periodical Articles

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