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Conventional inhibitors targeting the conserved SH2 domain of STAT3 have exhibited limited selectivity and efficacy. Here, we report that micheliolide (MCL), the active metabolite of the clinical-stage candidate ACT001, inhibits STAT3 through Cys367 (C367)-dependent covalent engagement within the DNA-binding domain (DBD)\u2013a residue unique to STAT3 among STAT family members. This specific modification disrupts STAT3 phosphorylation at Tyr705, nuclear translocation, and transcriptional activity prior to any detectable inhibition of upstream JAK phosphorylation, a finding that suggests that STAT3 inhibition is not primarily driven by upstream kinase blockade. Guided by covalent docking, R-group enumeration, and relative binding free-energy calculations via free-energy perturbation (FEP), we have designed and synthesized a series of MCL analogs. These derivatives retain comparable antiproliferative potency but exhibit markedly improved physicochemical properties, including enhanced kinetic aqueous solubility and optimized lipophilicity. Microscale thermophoresis confirms C367-dependent binding, while microsecond-scale molecular dynamics simulations and pair-interaction energy analyses highlight stable complexes in which electrostatic interactions predominate, with major contributions from key residues (Lys365, Val366, and Ile368). This study establishes C367 as a druggable covalent site in the historically challenging STAT3 DBD, validates FEP-guided optimization of covalent inhibitors, and identifies compound 16 as a promising next-generation lead with a superior drug-like profile for targeting STAT3-dependent cancers. All in all, these findings provide a foundation for advancing selective STAT3 DBD inhibitors toward clinical translation.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c03067","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:02:51Z","timestamp":1790236971000},"page":"12919-12934","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the \u201cUndruggable\u201d\nSTAT3 DBD:\nFree-Energy Perturbation-Guided Design of Covalent Micheliolide Derivatives\nTargeting Cysteine 367"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3664-0427","authenticated-orcid":true,"given":"Yangping","family":"Deng","sequence":"first","affiliation":[{"name":"Nankai University , , 94 Weijin Road , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8749-1702","authenticated-orcid":true,"given":"Hengwei","family":"Bian","sequence":"additional","affiliation":[{"name":"Nankai University , , 94 Weijin Road , ,","place":["Tianjin, China, 300071"]},{"name":"Nankai University, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology , , ,","place":["Tianjin, China, 300071"]},{"name":"Haihe Laboratory of Sustainable Chemical Transformations , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nankai University , , Haihe Education Park, 38 Tongyan Road , ,","place":["Tianjin, China, 300353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-0072","authenticated-orcid":true,"given":"Jianping","family":"Lin","sequence":"additional","affiliation":[{"name":"Nankai University , , Haihe Education Park, 38 Tongyan Road , ,","place":["Tianjin, China, 300353"]},{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]},{"name":"Nankai University , , ,","place":["Tianjin, China, 300353"]},{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , , 32 West seventh Avenue, Tianjin Airport Economic Area , ,","place":["Tianjin, China, 300308"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Li","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd ., ,","place":["Tianjin, China, 300193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-7097","authenticated-orcid":true,"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"Nankai University , , 94 Weijin Road , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4289-4829","authenticated-orcid":true,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Nankai University , , 94 Weijin Road , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5095-557X","authenticated-orcid":true,"given":"Jianshuang","family":"Guo","sequence":"additional","affiliation":[{"name":"Hebei University , , ,","place":["Baoding, China, 071002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0908-0046","authenticated-orcid":true,"given":"Haohao","family":"Fu","sequence":"additional","affiliation":[{"name":"Nankai University , , 94 Weijin Road , ,","place":["Tianjin, China, 300071"]},{"name":"Nankai University, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology , , ,","place":["Tianjin, China, 300071"]},{"name":"Haihe Laboratory of Sustainable Chemical Transformations , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2026101208081874700_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2024.109481","article-title":"Unraveling\nnew avenues in pancreatic cancer treatment: A comprehensive exploration\nof drug repurposing using transcriptomic data","volume":"185","author":"Sunildutt","year":"2025","journal-title":"Comput. 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Ther."},{"issue":"1","key":"2026101208081874700_cit5","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00430-1","article-title":"Targeting cancer stem\ncells for reversing therapy resistance: mechanism, signaling, and\nprospective agents","volume":"6","author":"Zhou","year":"2021","journal-title":"Signal Transduct. Target.\nTher."},{"issue":"4","key":"2026101208081874700_cit6","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70152","article-title":"STAT3 signaling pathway\nin health and disease","volume":"6","author":"Samad","year":"2025","journal-title":"MedComm"},{"issue":"15","key":"2026101208081874700_cit7","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7887","article-title":"Prognostic role of STAT3 in solid tumors: a systematic review and\nmeta-analysis","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"},{"issue":"4","key":"2026101208081874700_cit8","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2025.5734","article-title":"Tumor-associated\nneutrophils: Critical regulators in cancer progression and therapeutic\nresistance","volume":"66","author":"Hou","year":"2025","journal-title":"Int. J. Oncol."},{"key":"2026101208081874700_cit9","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1080\/13543776.2025.2494857","article-title":"Novel inhibitors of STAT3: an updated patent review\n(2022\u2013present)","volume":"35","author":"Bao","year":"2025","journal-title":"Expert Opin. Ther. Pat."},{"issue":"8","key":"2026101208081874700_cit10","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1038\/s41388-020-01626-z","article-title":"Targeting STAT3 by a small molecule suppresses\npancreatic cancer\nprogression","volume":"40","author":"Chen","year":"2021","journal-title":"Oncogene"},{"key":"2026101208081874700_cit11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cclet.2024.110447","article-title":"Small molecular\ninhibitors and degraders targeting STAT3 for cancer therapy: An updated\nreview (from 2022 to 2024)","volume":"36","author":"Kang","year":"2025","journal-title":"Chin. Chem. Lett."},{"issue":"5707","key":"2026101208081874700_cit12","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1126\/science.1105166","article-title":"Stat3 dimerization\nregulated by reversible acetylation of a single lysine residue","volume":"307","author":"Yuan","year":"2005","journal-title":"Science"},{"issue":"5","key":"2026101208081874700_cit13","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17050755","article-title":"Targeting\nSTAT3 for Cancer Therapy:\nFocusing on Y705, S727, or Dual Inhibition?","volume":"17","author":"Berkley","year":"2025","journal-title":"Cancers"},{"issue":"17","key":"2026101208081874700_cit14","doi-asserted-by":"publisher","first-page":"14192","DOI":"10.1074\/jbc.M111.323899","article-title":"Mechanisms of unphosphorylated\nSTAT3 transcription factor binding to DNA","volume":"287","author":"Timofeeva","year":"2012","journal-title":"J.\nBiol. Chem."},{"issue":"6","key":"2026101208081874700_cit15","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/onc.2015.215","article-title":"Small-molecule inhibitors targeting the DNA-binding\ndomain of STAT3 suppress tumor growth, metastasis and STAT3 target\ngene expression in vivo","volume":"35","author":"Huang","year":"2016","journal-title":"Oncogene"},{"issue":"17","key":"2026101208081874700_cit16","doi-asserted-by":"publisher","first-page":"10002","DOI":"10.1021\/acs.chemrev.9b00063","article-title":"Comprehensive structure\u2013activity\nrelationship studies of macrocyclic\nnatural products enabled by their total syntheses","volume":"119","author":"Itoh","year":"2019","journal-title":"Chem. Rev."},{"key":"2026101208081874700_cit17","doi-asserted-by":"publisher","first-page":"6309","DOI":"10.1021\/acs.chemrev.4c00969","article-title":"Computer-Aided Drug Discovery for\nUndruggable Targets","volume":"125","author":"Sun","year":"2025","journal-title":"Chem. 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Chem."},{"issue":"2","key":"2026101208081874700_cit20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116202","article-title":"Micheliolide\nderivative DMAMCL inhibits glioma cell growth in vitro and in vivo","volume":"10","author":"An","year":"2015","journal-title":"PLoS One"},{"key":"2026101208081874700_cit21","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1551115","article-title":"Sesquiterpene lactones and cancer:\nnew insight into\nantitumor and anti-inflammatory effects of parthenolide-derived Dimethylaminomicheliolide\nand Micheliolide","volume":"16","author":"Li","year":"2025","journal-title":"Front. Pharmacol."},{"issue":"10","key":"2026101208081874700_cit22","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1986-2","article-title":"ACT001, a novel PAI-1 inhibitor,\nexerts synergistic effects in combination\nwith cisplatin by inhibiting PI3K\/AKT pathway in glioma","volume":"10","author":"Xi","year":"2019","journal-title":"Cell Death Dis."},{"issue":"1","key":"2026101208081874700_cit23","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1182\/blood-2022-165225","article-title":"Micheliolide\nExerts Therapeutic Effect in Myeloproliferative Neoplasms through\nBinding to STAT3 and STAT5 Proteins and Inhibiting Their Activities","volume":"140","author":"Huang","year":"2022","journal-title":"Blood"},{"issue":"04","key":"2026101208081874700_cit24","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1097\/BS9.0000000000000168","article-title":"Micheliolide\nexerts effects in myeloproliferative neoplasms through inhibiting\nSTAT3\/5 phosphorylation via covalent binding to STAT3\/5 proteins","volume":"5","author":"Huang","year":"2023","journal-title":"Blood Sci."},{"key":"2026101208081874700_cit25","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1265177","article-title":"ACT001\nimproved cardiovascular function in septic mice by inhibiting the\nproduction of proinflammatory cytokines and the expression of JAK-STAT\nsignaling pathway","volume":"14","author":"Peng","year":"2023","journal-title":"Front. 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ACT001\u2013A promising\ntherapeutic for diffuse\nintrinsic pontine gliomas","volume":"23","author":"Upton","year":"2021","journal-title":"Neuro-oncol."},{"issue":"21","key":"2026101208081874700_cit29","doi-asserted-by":"publisher","first-page":"6654","DOI":"10.1021\/jm800524s","article-title":"Hit identification\nand binding mode predictions by\nrigorous free energy simulations","volume":"51","author":"Michel","year":"2008","journal-title":"J. Med. Chem."},{"issue":"3","key":"2026101208081874700_cit30","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1021\/acs.jmedchem.7b00681","article-title":"Free energy methods in drug design:\nprospects of \u201calchemical perturbation\u201d in medicinal\nchemistry: miniperspective","volume":"61","author":"Williams-Noonan","year":"2018","journal-title":"J. Med. 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Commun."},{"issue":"9","key":"2026101208081874700_cit33","doi-asserted-by":"publisher","first-page":"3782","DOI":"10.1021\/acs.jcim.9b00367","article-title":"Reaction-based\nenumeration, active learning, and free energy calculations to rapidly\nexplore synthetically tractable chemical space and optimize potency\nof cyclin-dependent kinase 2 inhibitors","volume":"59","author":"Konze","year":"2019","journal-title":"J.\nChem. Inf. Model."},{"issue":"4","key":"2026101208081874700_cit34","doi-asserted-by":"publisher","DOI":"10.1063\/5.0014475","article-title":"Scalable\nmolecular dynamics on CPU and GPU architectures\nwith NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"issue":"5","key":"2026101208081874700_cit35","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRev.36.823","article-title":"On the theory of the Brownian motion","volume":"36","author":"Uhlenbeck","year":"1930","journal-title":"Phys. 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Comput.\nChem."},{"key":"2026101208081874700_cit39","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N log (N)\nmethod for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem.\nPhys."},{"issue":"3","key":"2026101208081874700_cit40","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1063\/1.463137","article-title":"Reversible multiple time scale molecular\ndynamics","volume":"97","author":"Tuckerman","year":"1992","journal-title":"J. Chem. Phys."},{"issue":"21","key":"2026101208081874700_cit41","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1002\/jcc.24829","article-title":"CHARMM-GUI\nligand reader and modeler for CHARMM force field generation\nof small molecules","volume":"38","author":"Kim","year":"2017","journal-title":"J. Comput. 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