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The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in\u2005vitro by SPR experiments to be in the \u223c30\u201050\u2005\u03bcM K<jats:sub>d<\/jats:sub> range (Amson et\u2005al. Nature Med 2012), supporting a TCTP\u2010dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on\u2010going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk\u20101 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure\/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent \u223cmM K<jats:sub>d<\/jats:sub> and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature.<\/jats:p>","DOI":"10.1002\/cmdc.202100528","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T05:41:43Z","timestamp":1630561303000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Revisiting the Molecular Interactions between the Tumor Protein TCTP and the Drugs Sertraline\/Thioridazine"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4908-1588","authenticated-orcid":false,"given":"Florian","family":"Malard","sequence":"first","affiliation":[{"name":"Institut de Chimie des Substances Naturelles CNRS, Universit\u00e9 Paris-Saclay  1 av. de la terrasse 91198 Gif-sur-Yvette France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6366-8436","authenticated-orcid":false,"given":"Eric","family":"Jacquet","sequence":"additional","affiliation":[{"name":"Institut de Chimie des Substances Naturelles CNRS, Universit\u00e9 Paris-Saclay  1 av. de la terrasse 91198 Gif-sur-Yvette France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naima","family":"Nhiri","sequence":"additional","affiliation":[{"name":"Institut de Chimie des Substances Naturelles CNRS, Universit\u00e9 Paris-Saclay  1 av. de la terrasse 91198 Gif-sur-Yvette France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5760-2614","authenticated-orcid":false,"given":"Christina","family":"Sizun","sequence":"additional","affiliation":[{"name":"Institut de Chimie des Substances Naturelles CNRS, Universit\u00e9 Paris-Saclay  1 av. de la terrasse 91198 Gif-sur-Yvette France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Am\u00e9lie","family":"Chabrier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, BioCIS Facult\u00e9 de Pharmacie, CNRS  92290 Ch\u00e2tenay-Malabry France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4994-9001","authenticated-orcid":false,"given":"Samir","family":"Messaoudi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, BioCIS Facult\u00e9 de Pharmacie, CNRS  92290 Ch\u00e2tenay-Malabry France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-2959","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Dejeu","sequence":"additional","affiliation":[{"name":"Univ. 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