Abstract 1751: Beta catenin c-mods are orally bioavailable small-molecules targeting Wnt-driven tumors

Abstract Constitutive activation of the Wnt/beta catenin pathway drives malignancy in a wide range of cancers. The oncogenic transcription factor beta catenin has been notoriously difficult to target due to its disordered nature and lack of defined drug-binding pockets. Using Dewpoint’s proprietary AI/ML-powered discovery platform, we have identified and optimized small molecule condensate modulators (c-mods) that act via a novel mechanism of action, sequestering beta catenin into inactive condensate depots. Sequestering beta catenin into nuclear condensates selectively inhibits beta catenin-driven transcription and induces robust cancer cell death. The development candidate DPTX3186 is an orally bioavailable small molecule that demonstrates strong anti-tumor activity across multiple tumor types driven by various defects along the Wnt/beta catenin pathway and modulates Wnt pathway activity in vivo. Profound pharmacological efficacy, including regressions and complete responses, has been observed in murine models of gastric cancer. Collectively, these findings highlight the potential of condensate biology to target previously undruggable, high-value oncology targets, paving the way for novel treatments for patients with significant unmet medical needs. Citation Format: Isaac Klein, Kip West, Doug Baumann, Adam Talbot, Thomas Durand-Reville, Karl Hsu, Ann Boija. Beta catenin c-mods are orally bioavailable small-molecules targeting Wnt-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1751.