Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer
The incidence and mortality of high-grade endometrial cancers are increasing, and heterozygous hotspot mutations in PPP2R1A are drivers of the most aggressive forms of uterine cancer. PPP2R1A encodes the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. These recurrent mutations, specifically at the Pro 179 and Ser 256 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 179 →Arg) and S256F (Ser 256 →Phe) mutants. A small-molecule library was designed to fit into the pocket at the binding interface of the Aα/B56α/C heterotrimer. The lead molecule, RPT04402, promoted B56α heterotrimerization to the Aα P179R and Aα S256F 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 B56α. Combined, these data demonstrate that PP2A molecular glues are a promising first-in-class therapy that might benefit patients with PPP2R1A mutant uterine cancer by targeting a driver of this aggressive disease.
Authors
- Derek J. Taylor (ORCID: https://orcid.org/0000-0001-9932-1856)
- Brynne Raines (ORCID: https://orcid.org/0000-0003-0877-8266)
- Irene Peris (ORCID: https://orcid.org/0000-0003-4611-3855)
- Wei Huang (ORCID: https://orcid.org/0000-0003-2097-8148)
- Silvia Romero-Murillo (ORCID: https://orcid.org/0000-0001-7020-5819)
- Obdulia Rabal (ORCID: https://orcid.org/0000-0002-3224-0987)
- Olga Gherbovet
- Alexis Harold (ORCID: https://orcid.org/0000-0002-1810-5148)
- Jaya Sangodkar
- Caitlin M. O’Connor (ORCID: https://orcid.org/0000-0002-7840-6399)
- Terrance James Haanen (ORCID: https://orcid.org/0000-0003-1461-3169)
- Laura Fourmois
- George L. Trainor (ORCID: https://orcid.org/0000-0002-9730-1891)
- Daniel Léonard (ORCID: https://orcid.org/0000-0002-3362-0367)
- Shirish Shenolikar (ORCID: https://orcid.org/0000-0003-0540-6328)
- Varsha Shankar (ORCID: https://orcid.org/0000-0002-3633-6230)
- Goutham Narla (ORCID: https://orcid.org/0000-0003-4098-4203)
- David L. Brautigan (ORCID: https://orcid.org/0000-0003-1687-5250)
- Frédéric Cachoux (ORCID: https://orcid.org/0009-0007-2651-7875)
- Analisa DiFeo (ORCID: https://orcid.org/0000-0001-8319-6763)
- Kaitlin P. Zawacki (ORCID: https://orcid.org/0000-0001-7054-2532)
- Charles A. Nino (ORCID: https://orcid.org/0000-0001-9436-1568)
- Sophie Boock (ORCID: https://orcid.org/0009-0007-8247-5630)
- Jiang Hu (ORCID: https://orcid.org/0000-0003-4284-2575)
- Brian Tran (ORCID: https://orcid.org/0000-0001-9871-0980)
- Catherine G. Callahan (ORCID: https://orcid.org/0009-0008-2940-9770)
- Gabrielle Hodges Onishi (ORCID: https://orcid.org/0009-0004-8095-3668)
- Matthew Hinderman (ORCID: https://orcid.org/0009-0008-1038-3224)
- Amanda C. Dowdican (ORCID: https://orcid.org/0009-0002-1088-157X)
- Miranda Giambi
- Leah Arbitman
- Kelsey Barrie (ORCID: https://orcid.org/0009-0003-7551-4487)
- Alexander Day (ORCID: https://orcid.org/0000-0003-4926-7059)
Institutions
- University of Michigan (US)
- Michigan Medicine (US)
- Michigan Cancer Research Consortium (US)
- Signature Research (United States) (US)
- University of Virginia (US)
- Case Western Reserve University (US)
- Universidad de Navarra (ES)
- Evotec (United States) (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1126/scitranslmed.ady4852
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- National Institutes of Health
- National Cancer Institute