Abstract B105: Oral small molecule MYC condensate modulators (c-mods) induce robust anti-tumor responses in preclinical solid tumor models

Abstract MYC is a well-known tumor driver, frequently amplified or overexpressed in various human cancers. Despite its pivotal role in oncogenesis, MYC is considered an "undruggable" target due to its high degree of disorder, the absence of well-defined drug binding pockets and its dependence on highly dynamic interactions for its function. Here, we show the discovery of small molecule condensate modulators (c-mods) that inhibit MYC oncogenic function. MYC c-mods were identified using Dewpoint’s AI/ML and condensate science powered technology. The c-mods selectively dissolve MYC nuclear condensates, repress the expression of MYC target genes and induce cell cycle arrest, apoptosis and MYC-dependent killing of cancer cells. Cell line panel profiling shows a broad activity of MYC c-mods in a variety of solid tumor types. Advanced MYC c-mods are orally bioavailable and have drug-like properties. Single oral dose of MYC c-mod demonstrates a PK/PD relationship in reducing the levels of MYC protein and its downstream targets in tumors in an ovarian cancer cell line-derived xenograft (CDX) model. Orally dosed MYC c-mods yield tumor stasis or regression in ovarian and esophageal CDX models at tolerated daily doses. Together, our study demonstrates that targeted modulation of MYC condensates in cancer cells represents a promising therapeutic strategy for treating MYC-amplified or -overexpressed human cancers. Citation Format: Bede Portz, Yingda Ye, Jianguo Ren, Alex Milot, Kip West, Thomas Durand-Reville, Isaac A. Klein, Ann Boija, Yufei Xu. Oral small molecule MYC condensate modulators (c-mods) induce robust anti-tumor responses in preclinical solid tumor models [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 B105.