Abstract B124: YTHDC1 inhibition as a therapeutic strategy with potent preclinical activity alone and in combination with BCL-2 inhibitors

Abstract YTHDC1 is an epigenetic reader of m6A-modified RNAs, which is increasingly recognized as an oncogenic driver, in acute myeloid leukemia (AML) and several solid cancers. YTHDC1 binds to m6A-modified RNAs and undergoes liquid–liquid phase separation to form nuclear biomolecular condensates, which are enriched in cancer cells but markedly reduced or absent in healthy CD34+ cells. These condensates stabilize oncogenic m6A-marked transcripts, including MYC and BCL2, protecting them from degradation. This promotes cancer cell growth and underscores the therapeutic potential of targeting YTHDC1 in cancers such as AML. Transition Bio has developed potent and highly selective small molecule inhibitors of YTHDC1 that block its interaction with m6A-modified RNAs and disrupt YTHDC1-driven biomolecular condensates in cells. Inhibition of YTHDC1 alters the expression of key oncogenes, including MYC, BCL2, and MCL1, and suppresses cancer cell growth both in vitro and in vivo in models of AML and small cell lung cancer (SCLC). To further understand the therapeutic potential of YTHDC1 inhibition, the activity of our inhibitors was explored in combination with standard of care and other rational combination agents based on the mechanism of action. Among agents tested, strong synergy was observed with the clinically approved BCL2 antagonist, Venetoclax, across a panel of AML cell lines. Notably, the combination demonstrated synergy in both Venetoclax-sensitive and -resistant AML cell lines, underscoring its potential utility across a broad spectrum of disease subtypes. Synergistic combinatorial activity was also observed in vivo, producing tumor regressions with the combination of sub-efficacious doses of each agent. Together, our data provide a rationale for the clinical development of YTHDC1 inhibition both as a single agent and in combination with standard-of-care treatments, including BCL2 inhibitors. Citation Format: Richard C. Centore, Mark Charles, Mansi Arora, Marius Rebmann, Jerome Cattin, Alexander Howarth, Nagakumar Bharatham, Michael Rawling, Prathima Radhakrishnan, Seema Qamar, Matthew Watson, Laura Andraghetti, Andrew Seeber, Samuel Cohen, Martin Kulander, Tuomas Knowles, Shilpi Arora. YTHDC1 inhibition as a therapeutic strategy with potent preclinical activity alone and in combination with BCL-2 inhibitors [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 B124.