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Transl. Med."],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:p>\n                    The incidence and mortality of high-grade endometrial cancers are increasing, and heterozygous hotspot mutations in\n                    <jats:italic toggle=\"yes\">PPP2R1A<\/jats:italic>\n                    are drivers of the most aggressive forms of uterine cancer.\n                    <jats:italic toggle=\"yes\">PPP2R1A<\/jats:italic>\n                    encodes the A\u03b1 scaffolding subunit of the heterotrimeric phosphatase PP2A. These recurrent mutations, specifically at the Pro\n                    <jats:sup>179<\/jats:sup>\n                    and Ser\n                    <jats:sup>256<\/jats:sup>\n                    residues, disrupt the binding of tumor-suppressive substrate-directing B56 and B55 subunits to the PP2A scaffolding subunit while maintaining binding to other regulatory subunits. Here, we identified a series of molecular glues that correct PP2A trimer formation in the context of the P179R (Pro\n                    <jats:sup>179<\/jats:sup>\n                    \u2192Arg) and S256F (Ser\n                    <jats:sup>256<\/jats:sup>\n                    \u2192Phe) mutants. A small-molecule library was designed to fit into the pocket at the binding interface of the A\u03b1\/B56\u03b1\/C heterotrimer. The lead molecule, RPT04402, promoted B56\u03b1 heterotrimerization to the A\u03b1\n                    <jats:sup>P179R<\/jats:sup>\n                    and A\u03b1\n                    <jats:sup>S256F<\/jats:sup>\n                    mutant scaffolds. In mice, RPT04402 treatment drove tumor regressions and extended median survival in multiple independent mutant cell lines and patient-derived xenografts, proving a robust single-agent activity. This activity was abrogated upon knockout of B56\u03b1. Combined, these data demonstrate that PP2A molecular glues are a promising first-in-class therapy that might benefit patients with\n                    <jats:italic toggle=\"yes\">PPP2R1A<\/jats:italic>\n                    mutant uterine cancer by targeting a driver of this aggressive disease.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ady4852","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:58:41Z","timestamp":1792000721000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Restoration of PP2A A\u03b1B56\u03b1C trimer formation by RPT04402 molecular glue in high-grade uterine cancer"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-3855","authenticated-orcid":true,"given":"Irene","family":"Peris","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1461-3169","authenticated-orcid":true,"suffix":"III","given":"Terrance J.","family":"Haanen","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."},{"name":"Department of Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4926-7059","authenticated-orcid":true,"given":"Alexander","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2940-9770","authenticated-orcid":true,"given":"Catherine","family":"Callahan","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8095-3668","authenticated-orcid":true,"given":"Gabrielle","family":"Hodges-Onishi","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7054-2532","authenticated-orcid":true,"given":"Kaitlin P.","family":"Zawacki","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9871-0980","authenticated-orcid":true,"given":"Brian","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."},{"name":"Rogel Cancer Center, University of Michigan 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