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The calcium-binding protein S100A4 can induce cell migration\/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 \u00b5M) and human (56 \u00b5M) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb\/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10\u2013100 nM concentration range (Fisher\u2019s Exact test, p \u2264 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.<\/jats:p>","DOI":"10.3390\/biom13071099","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T01:40:02Z","timestamp":1689039602000},"page":"1099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Thamir M.","family":"Ismail","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel G.","family":"Crick","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology and Immunity, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Shivkumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Carnell","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-1194","authenticated-orcid":false,"given":"Roger","family":"Barraclough","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-3548","authenticated-orcid":false,"given":"Guozheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology and Immunity, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Medical School, Southeast University, Nanjing 230032, China"},{"name":"Department of Gastroenterology, First Affiliated Hospital, Anhui Medical University, Hefei 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-3104","authenticated-orcid":false,"given":"Weiping","family":"Yu","sequence":"additional","affiliation":[{"name":"Medical School, Southeast University, Nanjing 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Platt-Higgins","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9730-0960","authenticated-orcid":false,"given":"Gemma","family":"Nixon","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Rudland","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"key":"ref_1","unstructured":"International Association of Cancer Research. 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