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Approximately 30%\u201340% of breast cancers harbor mutations in the\n                    <jats:italic>TP53<\/jats:italic>\n                    gene, leading to structural and functional alterations in the p53 protein. These changes result in mutant proteins that are unable to perform their canonical tumor suppressor functions and, in many cases, exhibit gain\u2010of\u2010function properties, making mutant p53 a highly attractive therapeutic target. Among these mutations, R280K and R273H are two clinically relevant DNA\u2010binding mutations. In this study, we extended our investigation of the (\n                    <jats:italic>R<\/jats:italic>\n                    )\u2010tryptophanol isoindolinone derivative\n                    <jats:bold>RVJB59<\/jats:bold>\n                    to these two p53 mutants. Differential scanning fluorimetry showed that\n                    <jats:bold>RVJB59<\/jats:bold>\n                    thermally stabilized the R280K mutant p53 in a dose\u2010dependent manner. Furthermore, the mechanism of action of\n                    <jats:bold>RVJB59<\/jats:bold>\n                    was investigated by liquid chromatography coupled with high\u2010resolution tandem mass spectrometry (LC\u2013HRMS\/MS) using the DNA\u2011binding domains of the R280K and R273H mutants, confirming covalent binding of the compound to Cys141 in both proteins. Computational studies with both p53 mutants suggested that\n                    <jats:bold>RVJB59<\/jats:bold>\n                    can stably bind in proximity to Cys141, further reinforcing the results obtained by LC\u2013HRMS\/MS. Our findings further underscore the potential of\n                    <jats:bold>RVJB59<\/jats:bold>\n                    for the development of novel therapies for the treatment of breast cancers harboring these mutations.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70483","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T03:00:54Z","timestamp":1788663654000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59"],"prefix":"10.1002","volume":"21","author":[{"given":"Ricardo J. F.","family":"Ferreira","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6799-2740","authenticated-orcid":false,"given":"L\u00eddia M.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-1254","authenticated-orcid":false,"given":"Mattia","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Chemistry and Pharmacy University of Siena  Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-7369","authenticated-orcid":false,"given":"Alexandra M. M.","family":"Antunes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural \u2013 Institute of Molecular Sciences Departamento de Engenharia Qu\u00edmica Instituto Superior T\u00e9cnico Universidade de Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-9342","authenticated-orcid":false,"given":"Ana P.","family":"Leandro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-9353","authenticated-orcid":false,"given":"Maria M. 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