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journal article·2025-02Open access

Novel Naphthyridones Targeting Pannexin 1 for Colitis Management

Wen‐Yun Hsueh, Yi‐Ling Wu, Meng‐Tzu Weng, Shin‐Yun Liu, Jascinta P Santavanond, Yi‐Chung Liu, Ching‐I Lin, Cheng‐Nong Lai, Yi‐Ru Lu, Jing Yin Hsu, Hong‐Yu Gao, Jinq‐Chyi Lee, Shu‐Chen Wei, Ping‐Chiang Lyu, Ivan K H Poon, Hsing‐Pang Hsieh, Yu‐Hsin Chiu

Advanced Science· Volume 12· Issue 7
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Source abstract

Abstract

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 IC 50 of 0.73 µ 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.
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Research context

OpenAlex topics: Connexins and lens biology · Ion Channels and Receptors · Biochemical effects in animals

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemistry National Tsing Hua University Hsinchu 300044 Taiwan

Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Miaoli County 350401 Taiwan

Institute of Biotechnology National Tsing Hua University Hsinchu 300044 Taiwan

Department of Internal Medicine National Taiwan University Hospital Taipei City 100229 Taiwan

Department of Medical Research National Taiwan University Hospital Hsin‐Chu Branch Hsinchu 302058 Taiwan

Department of Biochemistry and Chemistry La Trobe Institute for Molecular Science La Trobe University Melbourne VIC 3086 Australia

Research Centre for Extracellular Vesicles La Trobe University VIC 3086 Australia

Institute of Population Health Sciences National Health Research Institutes Miaoli County 350401 Taiwan

Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu 300044 Taiwan

Departments of Medical Science, Life Science, and Medicine National Tsing Hua University Hsinchu 300044 Taiwan

Funding

National Science and Technology Council · National Taiwan University Hospital · National Health Research Institutes

References (71)

Show source-provided references
1. 10.1038/nature0878010.1038/nature08780 ↗
2. 10.1016/j.immuni.2017.06.02010.1016/j.immuni.2017.06.020 ↗
3. 10.1002/bies.20140002410.1002/bies.201400024 ↗
4. 10.1242/jcs.00951410.1242/jcs.009514 ↗
5. 10.1038/s41586-020-2121-310.1038/s41586-020-2121-3 ↗
6. 10.7554/eLife.6478710.7554/eLife.64787 ↗
7. 10.1038/nature0941310.1038/nature09413 ↗
8. 10.1161/CIRCRESAHA.117.31238010.1161/CIRCRESAHA.117.312380 ↗
9. 10.1016/j.molmet.2015.06.00910.1016/j.molmet.2015.06.009 ↗
10. 10.1126/scitranslmed.aar379610.1126/scitranslmed.aar3796 ↗
11. 10.1038/srep4255010.1038/srep42550 ↗
12. 10.1042/BST2023003810.1042/BST20230038 ↗
13. 10.1038/nm.267910.1038/nm.2679 ↗
14. 10.1021/acschemneuro.0c0033310.1021/acschemneuro.0c00333 ↗
15. 10.1038/nrgastro.2015.15010.1038/nrgastro.2015.150 ↗
16. 10.1038/nrgastro.2016.20810.1038/nrgastro.2016.208 ↗
17. 10.3389/fphar.2018.0086510.3389/fphar.2018.00865 ↗
18. 10.1111/j.1471-4159.2004.02947.x10.1111/j.1471-4159.2004.02947.x ↗
19. 10.1152/ajpcell.00227.200810.1152/ajpcell.00227.2008 ↗
20. 10.3109/1541906100364261810.3109/15419061003642618 ↗
21. 10.1038/sj.emboj.760137810.1038/sj.emboj.7601378 ↗
22. 10.1002/bies.20080023610.1002/bies.200800236 ↗
23. 10.1038/nature1314710.1038/nature13147 ↗
24. 10.1186/s12974-018-1069-910.1186/s12974-018-1069-9 ↗
25. 10.1056/NEJM20000203342051710.1056/NEJM200002033420517 ↗
26. 10.1074/jbc.M111.32337810.1074/jbc.M111.323378 ↗
27. 10.1038/ncomms1432410.1038/ncomms14324 ↗
28. 10.1021/tx700308510.1021/tx7003085 ↗
29. 10.1038/s41419-024-06513-z10.1038/s41419-024-06513-z ↗
30. 10.1085/jgp.20151150510.1085/jgp.201511505 ↗
31. 10.1038/s41586-020-2357-y10.1038/s41586-020-2357-y ↗
32. 10.1038/s41594-020-0401-010.1038/s41594-020-0401-0 ↗
33. 10.7554/eLife.5467010.7554/eLife.54670 ↗
34. 10.1038/nprot.2014.13810.1038/nprot.2014.138 ↗
35. 10.1021/acschembio.9b0039910.1021/acschembio.9b00399 ↗
36. 10.1002/jcc.2133410.1002/jcc.21334 ↗
37. 10.1093/nar/gkab29410.1093/nar/gkab294 ↗
38. 10.1021/ci200227u10.1021/ci200227u ↗
39. 10.1002/bies.20110017310.1002/bies.201100173 ↗
40. 10.1016/j.cell.2014.03.02410.1016/j.cell.2014.03.024 ↗
41. 10.1126/science.125282610.1126/science.1252826 ↗
42. 10.1016/j.cell.2015.12.03110.1016/j.cell.2015.12.031 ↗
43. 10.1016/j.jmb.2021.16699410.1016/j.jmb.2021.166994 ↗
44. 10.1126/sciadv.ade993110.1126/sciadv.ade9931 ↗
45. 10.1002/advs.20240108510.1002/advs.202401085 ↗
46. 10.1016/S0014-5793(01)02561-310.1016/S0014-5793(01)02561-3 ↗
47. 10.1124/jpet.114.21418910.1124/jpet.114.214189 ↗
48. 10.1038/s41467-021-24825-y10.1038/s41467-021-24825-y ↗
49. 10.1016/j.immuni.2024.03.00210.1016/j.immuni.2024.03.002 ↗
50. 10.1016/j.yjmcc.2012.04.01110.1016/j.yjmcc.2012.04.011 ↗
51. 10.2165/00003088-198106020-0000410.2165/00003088-198106020-00004 ↗
52. Khan M. · Am. J. Transl. Res. · 2020 · 12 · 4074
53. 10.1038/nm.428110.1038/nm.4281 ↗
54. 10.1038/ncb319410.1038/ncb3194 ↗
55. 10.1152/ajpcell.00097.200710.1152/ajpcell.00097.2007 ↗
56. 10.1085/jgp.20171188810.1085/jgp.201711888 ↗
57. 10.1021/acs.jmedchem.3c0111610.1021/acs.jmedchem.3c01116 ↗
58. 10.3390/ijms2403202210.3390/ijms24032022 ↗
59. 10.1074/jbc.TM118.00334410.1074/jbc.TM118.003344 ↗
60. 10.3389/fnins.2016.0031110.3389/fnins.2016.00311 ↗
61. 10.1007/s11302-021-09804-810.1007/s11302-021-09804-8 ↗
62. 10.1038/srep3984610.1038/srep39846 ↗
63. 10.1038/nprot.2016.02810.1038/nprot.2016.028 ↗
64. 10.1093/nar/28.1.23510.1093/nar/28.1.235 ↗
65. 10.1007/978-1-4939-2269-7_1910.1007/978-1-4939-2269-7_19 ↗
66. 10.1097/MIB.000000000000125010.1097/MIB.0000000000001250 ↗
67. B.Chassaing J. D.Aitken M.Malleshappa M.Vijay‐Kumar Curr. Protoc. Immunol.2014 104 15.25.1.10.1002/0471142735.im1525s104 ↗
68. 10.1097/01.MIB.0000164017.06538.8a10.1097/01.MIB.0000164017.06538.8a ↗
69. 10.1038/s41385-019-0189-610.1038/s41385-019-0189-6 ↗
70. 10.1016/j.phrs.2023.10664610.1016/j.phrs.2023.106646 ↗
71. 10.3390/biom1110152310.3390/biom11101523 ↗