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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,6,18]]},"abstract":"<jats:p>\n                    Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex\n                    <jats:bold>1a<\/jats:bold>\n                    , which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound\n                    <jats:bold>1a<\/jats:bold>\n                    effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of\n                    <jats:bold>1a<\/jats:bold>\n                    in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably,\n                    <jats:bold>1a<\/jats:bold>\n                    exhibits high binding affinity to Girdin with a K\n                    <jats:sub>d<\/jats:sub>\n                    of 1.3 \u03bcM and targets the Girdin-linked EGFR\/AKT\/mTOR\/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2316615121","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T13:57:03Z","timestamp":1718114223000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers"],"prefix":"10.1073","volume":"121","author":[{"given":"Mei-Ling","family":"Ruan","sequence":"first","affiliation":[{"name":"Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong Science Park, Shatin, Hong Kong, China"},{"name":"State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Pokfulam, Hong Kong, China"},{"name":"National Key Laboratory of Green Pesticide, College of Chemistry, Central China Normal University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Xiu","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Shantou University Medical College, Shantou 515041, Guangdong, China"},{"name":"Chemistry and Chemical Engineering of Guangdong Laboratory, Shantou 515041, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3312","authenticated-orcid":false,"given":"Jacky C. 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