Abstract B051: Discovery of SW-3431, a first-in-class molecular glue activator with potent and selective anti-tumor activity in PPP2R1A mutant cancers

Abstract Uterine cancer is the only cancer type for which survival has fallen in the past four decades. This past year, uterine cancer deaths surpassed ovarian cancer for the first time: making uterine cancer the deadliest gynecological cancer. Mortality from uterine cancer is primarily due to the aggressive, high-grade subtypes of endometrial cancer. Molecularly, these tumors are hallmarked by copy number alterations, however, almost every uterine serous carcinoma tumor harbors a TP53 mutation, and 30-40% of tumors also harbor co-occurrent driver mutations to PPP2R1A. These heterozygous mutations occur at hotspot sites, most commonly P179R and S256F. Currently, no targeted therapies exist for high-grade uterine cancers. PPP2R1A encodes for the Aα scaffolding subunit of the heterotrimeric serine/threonine phosphatase Protein Phosphatase 2A (PP2A). The PP2A heterotrimeric complex is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate-directing regulatory (B) subunit. We have shown that these scaffolding mutations cause a biased pool of heterotrimers, abrogating the formation of tumor-suppressive holoenzymes while leaving tumor-promoting heterotrimers intact. We sought to target this molecular alteration using a molecular glue to correct trimer formation to the mutant scaffold. Using the high resolution cryo-EM structure of the tumor suppressive PP2A Aα/B56α/Cα heterotrimer developed by our team, we designed and synthesized a small molecule library to fit into a key binding interface between Aα/B56α/Cα subunits. Here, we report the identification of SW-3431 which increases the affinity of B56α to the AαP179R and AαS256F mutant scaffolds in both biophysical and cell based models. In multiple CDX and PDX models of PPP2R1A mutant uterine cancer, SW-3431 treatment drove tumor regressions and median survival extensions. Importantly, this activity was abrogated upon knockout of B56α demonstrating a high degree of target specificity to this specific PP2A heterotrimer. Combined, these data demonstrate that PP2A molecular glues are a promising novel therapy for PPP2R1A mutant uterine cancer patients and represent the first small molecule approach targeting a driver of this aggressive disease. Citation Format: Goutham Narla, Irene Peris, George Trainor, Frederic Cachoux, Analisa DiFeo, Derek Taylor, Caitlin M. O'Connor. Discovery of SW-3431, a first-in-class molecular glue activator with potent and selective anti-tumor activity in PPP2R1A mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B051.