{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:48:24Z","timestamp":1791827304722,"version":"4.3.4"},"reference-count":50,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22401192"],"award-info":[{"award-number":["22401192"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U25A20597"],"award-info":[{"award-number":["U25A20597"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1016\/j.ejmech.2026.119146","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T15:27:47Z","timestamp":1783783667000},"page":"119146","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Chirality-dependent toxicity decoupling: Discovery of a resibufogenin-based L-configured STING inhibitor with superior therapeutic profile for ulcerative colitis"],"prefix":"10.1016","volume":"318","author":[{"given":"Jia-Hua","family":"Zhuang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu-Heng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoujiao","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaopeng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Qiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiange","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu-Zhou","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"6","key":"10.1016\/j.ejmech.2026.119146_bib1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41577-024-01112-7","article-title":"Regulation of cGAS\u2013STING signalling and its diversity of cellular outcomes","volume":"25","author":"Zhang","year":"2025","journal-title":"Nat. Rev. Immunol."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib2","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1146\/annurev-immunol-101721-032910","article-title":"Regulation of the cGAS-STING pathway","volume":"43","author":"Zhang","year":"2025","journal-title":"Annu. Rev. Immunol."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119146_bib3","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1007\/s11427-024-2808-3","article-title":"cGAS-STING: mechanisms and therapeutic opportunities","volume":"68","author":"Zhang","year":"2025","journal-title":"Sci. China Life Sci."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13062-025-00611-4","article-title":"cGAS-STING targeting offers therapy choice in lung diseases","volume":"20","author":"Wang","year":"2025","journal-title":"Biol. Direct"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12964-023-01466-w","article-title":"cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation","volume":"22","author":"Liu","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"10.1016\/j.ejmech.2026.119146_bib6","doi-asserted-by":"crossref","DOI":"10.1016\/j.arr.2025.102691","article-title":"cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases","volume":"105","author":"Wang","year":"2025","journal-title":"Ageing Res. Rev."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13045-025-01691-5","article-title":"The cGAS\u2012STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications","volume":"18","author":"Shen","year":"2025","journal-title":"J. Hematol. Oncol."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s12943-025-02380-0","article-title":"Demystifying the cGAS-STING pathway: precision regulation in the tumor immune microenvironment","volume":"24","author":"Wang","year":"2025","journal-title":"Mol. Cancer"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib9","article-title":"cGAS--STING, an important signaling pathway in diseases and their therapy","volume":"5","author":"Li","year":"2024","journal-title":"MedComm"},{"issue":"9","key":"10.1016\/j.ejmech.2026.119146_bib10","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanisms and cellular functions of cGAS-STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"10.1016\/j.ejmech.2026.119146_bib11","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.2147\/DDDT.S501773","article-title":"Regulation and function of the cGAS-STING pathway: mechanisms, post-translational modifications, and therapeutic potential in immunotherapy","volume":"19","author":"Chen","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"issue":"13","key":"10.1016\/j.ejmech.2026.119146_bib12","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.3390\/molecules29133121","article-title":"Agonists and inhibitors of the cGAS-STING pathway","volume":"29","author":"Yu","year":"2024","journal-title":"Molecules"},{"issue":"7748","key":"10.1016\/j.ejmech.2026.119146_bib13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/s41586-019-1000-2","article-title":"Structural basis of STING binding with and phosphorylation by TBK1","volume":"567","author":"Zhang","year":"2019","journal-title":"Nature"},{"issue":"7758","key":"10.1016\/j.ejmech.2026.119146_bib14","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/s41586-019-1228-x","article-title":"A conserved PLPLRT\/SD motif of STING mediates the recruitment and activation of TBK1","volume":"569","author":"Zhao","year":"2019","journal-title":"Nature"},{"issue":"214","key":"10.1016\/j.ejmech.2026.119146_bib15","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2002521","article-title":"STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway","volume":"5","author":"Tanaka","year":"2012","journal-title":"Sci. Signal."},{"issue":"6227","key":"10.1016\/j.ejmech.2026.119146_bib16","doi-asserted-by":"crossref","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Science"},{"issue":"7748","key":"10.1016\/j.ejmech.2026.119146_bib17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41586-019-0998-5","article-title":"Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP","volume":"567","author":"Shang","year":"2019","journal-title":"Nature"},{"issue":"2","key":"10.1016\/j.ejmech.2026.119146_bib18","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2019.05.036","article-title":"STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition","volume":"178","author":"Ergun","year":"2019","journal-title":"Cell"},{"issue":"11","key":"10.1016\/j.ejmech.2026.119146_bib19","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41576-019-0151-1","article-title":"DNA sensing by the cGAS STING pathway in health and disease","volume":"20","author":"Motwani","year":"2019","journal-title":"Nat. Rev. Genet."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119146_bib20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri3850","article-title":"Aicardi\u2013Gouti\u00e8res syndrome and the type I interferonopathies","volume":"15","author":"Crow","year":"2015","journal-title":"Nat. Rev. Immunol."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119146_bib21","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.4049\/jimmunol.1500969","article-title":"Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi\u2013Gouti\u00e8res syndrome","volume":"195","author":"Gray","year":"2015","journal-title":"J. Immunol."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib22","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1038\/s41467-017-01932-3","article-title":"Type I interferon-mediated autoinflammation due to DNase II deficiency","volume":"8","author":"Rodero","year":"2017","journal-title":"Nat. Commun."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib23","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13024-025-00815-2","article-title":"The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease","volume":"20","author":"Quan","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"10.1016\/j.ejmech.2026.119146_bib24","doi-asserted-by":"crossref","DOI":"10.1016\/j.nbd.2024.106710","article-title":"The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases","volume":"202","author":"Zhang","year":"2024","journal-title":"Neurobiol. Dis."},{"key":"10.1016\/j.ejmech.2026.119146_bib25","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2025.114902","article-title":"cGAS-STING and neurodegenerative diseases: a molecular crosstalk and therapeutic perspective","volume":"159","author":"Dhapola","year":"2025","journal-title":"Int. Immunopharmacol."},{"issue":"9","key":"10.1016\/j.ejmech.2026.119146_bib26","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.4049\/jimmunol.1401337","article-title":"Intrinsic self-DNA triggers inflammatory disease dependent on STING","volume":"193","author":"Ahn","year":"2014","journal-title":"J. Immunol."},{"issue":"7713","key":"10.1016\/j.ejmech.2026.119146_bib27","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41586-018-0287-8","article-title":"Targeting STING with covalent small-molecule inhibitors","volume":"559","author":"Haag","year":"2018","journal-title":"Nature"},{"issue":"6","key":"10.1016\/j.ejmech.2026.119146_bib28","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJMoa1312625","article-title":"Activated STING in a vascular and pulmonary syndrome","volume":"371","author":"Liu","year":"2014","journal-title":"N. Engl. J. Med."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119146_bib29","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1021\/acs.jmedchem.4c02774","article-title":"Discovery of a novel CRBN-Recruiting cGAS PROTAC degrader for the treatment of ulcerative colitis","volume":"68","author":"He","year":"2025","journal-title":"J. Med. Chem."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119146_bib30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.molmed.2024.10.002","article-title":"cGAS-STING DNA-sensing in inflammatory bowel diseases","volume":"31","author":"Dimitrov","year":"2025","journal-title":"Trends Mol. Med."},{"issue":"13","key":"10.1016\/j.ejmech.2026.119146_bib31","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1016\/j.celrep.2017.11.101","article-title":"STING-dependent signaling underlies IL-10 controlled inflammatory colitis","volume":"21","author":"Ahn","year":"2017","journal-title":"Cell Rep."},{"issue":"9","key":"10.1016\/j.ejmech.2026.119146_bib32","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/s41419-021-04101-z","article-title":"Extracellular vesicles package dsDNA to aggravate Crohn's disease by activating the STING pathway","volume":"12","author":"Zhao","year":"2021","journal-title":"Cell Death Dis."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib33","first-page":"15","article-title":"Research progress of cGAS-STING signaling pathway modulators in Immunotherapy","volume":"55","author":"Lou","year":"2024","journal-title":"J. China Pharm. Univ."},{"issue":"8","key":"10.1016\/j.ejmech.2026.119146_bib34","article-title":"4-Octyl itaconate restricts STING activation by blocking its palmitoylation","volume":"42","author":"Su","year":"2023","journal-title":"Cell Rep."},{"issue":"12","key":"10.1016\/j.ejmech.2026.119146_bib35","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1007\/s11427-024-2703-6","article-title":"Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases","volume":"67","author":"Zhang","year":"2024","journal-title":"Sci. China Life Sci."},{"issue":"30","key":"10.1016\/j.ejmech.2026.119146_bib36","article-title":"Targeting STING oligomerization with small-molecule inhibitors","volume":"120","author":"Humphries","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA."},{"issue":"36","key":"10.1016\/j.ejmech.2026.119146_bib37","doi-asserted-by":"crossref","first-page":"20273","DOI":"10.1021\/jacs.3c03637","article-title":"Development of LB244, an irreversible STING antagonist","volume":"145","author":"Barasa","year":"2023","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1021\/acsmedchemlett.8b00466","article-title":"Discovery of a novel cGAMP competitive ligand of the inactive form of STING","volume":"10","author":"Siu","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"issue":"24","key":"10.1016\/j.ejmech.2026.119146_bib39","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2105465118","article-title":"STING inhibitors target the cyclic dinucleotide binding pocket","volume":"118","author":"Hong","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.ejmech.2026.119146_bib40","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2022.114975","article-title":"Gelsevirine improves age-related and surgically induced osteoarthritis in mice by reducing STING availability and local inflammation","volume":"198","author":"Feng","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.119146_bib41","doi-asserted-by":"crossref","first-page":"20723","DOI":"10.1021\/acs.jmedchem.4c02736","article-title":"Natural products driven medicinal chemistry","volume":"67","author":"Bharate","year":"2024","journal-title":"J. Med. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib42","first-page":"1","article-title":"Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity","volume":"20","author":"Wang","year":"2026","journal-title":"Mol. Oncol."},{"key":"10.1016\/j.ejmech.2026.119146_bib43","doi-asserted-by":"crossref","DOI":"10.1016\/j.redox.2024.103202","article-title":"Development of nitroalkene-based inhibitors to target STING-dependent inflammation","volume":"74","author":"Chang","year":"2024","journal-title":"Redox Biol."},{"key":"10.1016\/j.ejmech.2026.119146_bib44","doi-asserted-by":"crossref","DOI":"10.1016\/j.crchbi.2022.100028","article-title":"Stereochemical diversity as a source of discovery in chemical biology","volume":"2","author":"Scott","year":"2022","journal-title":"Curr. Res. Chem. Biol."},{"issue":"45","key":"10.1016\/j.ejmech.2026.119146_bib45","doi-asserted-by":"crossref","first-page":"33429","DOI":"10.1039\/D4RA05694A","article-title":"The significance of chirality in contemporary drug discovery-a mini review","volume":"14","author":"Senkuttuvan","year":"2024","journal-title":"RSC Adv."},{"key":"10.1016\/j.ejmech.2026.119146_bib46","doi-asserted-by":"crossref","first-page":"14185","DOI":"10.1021\/acs.langmuir.2c02199","article-title":"Integrative strategy for investigating the interactions between STING and small-molecule ligands","volume":"38","author":"Xu","year":"2022","journal-title":"Langmuir"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119146_bib47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/19420862.2021.1979800","article-title":"Antibody blockade of CD96 by distinct molecular mechanisms","volume":"13","author":"Lee","year":"2021","journal-title":"mAbs"},{"key":"10.1016\/j.ejmech.2026.119146_bib48","article-title":"Quinazoline-based dual-target inhibitors disrupt influenza virus rnp complex: rational design, synthesis and mechanistic validation of potent anti-influenza agents","volume":"301","author":"Zhang","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119146_bib49","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2025.117681","article-title":"Novel benzamide derivatives with indole moiety as dual-target antiviral agents: rational design, efficient synthesis, and potent anti-influenza activity through concurrent binding to pac terminal domain and viral nucleoprotein","volume":"293","author":"Zhang","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119146_bib50","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.chembiol.2026.04.001","article-title":"Identification of an STING inhibitor targeting the allosteric transmembrane domains","volume":"33","author":"Chen","year":"2026","journal-title":"Cell Chem. Biol."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S022352342600591X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S022352342600591X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:23:44Z","timestamp":1788049424000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S022352342600591X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11]]},"references-count":50,"alternative-id":["S022352342600591X"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119146","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Chirality-dependent toxicity decoupling: Discovery of a resibufogenin-based L-configured STING inhibitor with superior therapeutic profile for ulcerative colitis","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119146","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Published by Elsevier Masson SAS.","name":"copyright","label":"Copyright"}],"article-number":"119146"}}