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The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA\u2010binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53\u2010Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53\u2010Y220C surface cavity, and Zn\u2010binding fragments for metallochaperone activity. Their Zn\u2010binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds <jats:bold>L4<\/jats:bold> and <jats:bold>L5<\/jats:bold> to increase intracellular levels of Zn<jats:sup>2+<\/jats:sup> in a p53\u2010Y220C\u2010mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI\u201060), followed by testing in three stomach cancer cell lines with varying p53 status\u2019, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, <jats:bold>L5<\/jats:bold>, is nearly 3\u2010fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of <jats:bold>L5<\/jats:bold> is further maintained in a NUGC3 3D spheroid model. <jats:bold>L5<\/jats:bold> also induces Y220C\u2010specific apoptosis in a cleaved caspase\u20103 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild\u2010type function in mutant p53\u2010Y220C.<\/jats:p>","DOI":"10.1002\/chem.201802677","type":"journal-article","created":{"date-parts":[[2018,9,19]],"date-time":"2018-09-19T07:35:00Z","timestamp":1537342500000},"page":"17734-17742","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Multifunctional Compounds for Activation of the p53\u2010Y220C Mutant in Cancer"],"prefix":"10.1002","volume":"24","author":[{"given":"Jessica J.","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Chemistry Simon Fraser University  8888 University Drive Burnaby Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Orvain","sequence":"additional","affiliation":[{"name":"Inserm UMR_S 1113, Molecular Mechanisms of Stress Response and Pathologies Universit\u00e9 de Strasbourg  Strasbourg 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Boeckler and co-worker also report NUGC3-depedent induction of apoptosis after 6 hours at concentrations of 50 and 100\u2005\u03bcmfor PhiKan5196 and PhiKan5974 respectively (Ref.\u2005[8b]). 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