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While most small molecules developed to date have focused on typical C1 domains, the development of regulators targeting atypical C1 domains remains under\u2010explored. Herein, we describe the design and synthesis of novel cationic diacylglycerol DAG\u2010lactones to efficiently interact with the negatively charged residues present in the atypical C1 domain of Vav1, a guanine nucleotide exchange factor playing a critical role in tumor development, including pancreatic cancer. We evaluated the therapeutic potential of this new family of compounds using models from this dismal condition where Vav1 is aberrantly expressed. Treatment of cultured pancreatic tumor cells with\n                    <jats:italic>sn\u20101<\/jats:italic>\n                    cationic DAG\u2010lactones inhibited proliferation of Vav1\u2010expressing cells while Vav1\u2010negative cells showed no response. Additionally, we demonstrated that these compounds inhibited growth of patient\u2010derived organoids models of pancreatic cancer. These findings underscore the translational value of these cationic DAG\u2010lactones for pancreatic cancer patients expressing Vav1 and serve as foundation for future approaches targeting atypical C1 domain\u2010containing signaling proteins.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500589","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T23:03:37Z","timestamp":1761001417000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel DAG\u2010Lactone\u2010Based Vav1 Inhibitors Show Anti\u2010proliferative Activity in Pancreatic Cancer Models"],"prefix":"10.1002","volume":"20","author":[{"given":"Ana","family":"Bellomo","sequence":"first","affiliation":[{"name":"Departamento de Ingredientes Activos y Biorrefiner\u00edas Instituto Nacional de Tecnolog\u00eda Industrial  Av. General Paz N\u00ba 5445 San Mart\u00edn B1650WAB Buenos Aires Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET)  Buenos Aires C1425FQB Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Toruner","sequence":"additional","affiliation":[{"name":"Division of Oncology Research Department of Oncology Mayo Clinic  Rochester MN 55905 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Elhalem","sequence":"additional","affiliation":[{"name":"Departamento de Ingredientes Activos y Biorrefiner\u00edas Instituto Nacional de Tecnolog\u00eda Industrial  Av. 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