Abstract 453: Discovery of potent, selective, and orally bioavailable small molecule inhibitors of YTHDC1 for the treatment of MYC-driven cancers

Abstract The MYC family of oncogenes (including c-MYC, L-MYC, and N-MYC) has been considered one of the most sought-after drug targets in oncology. These transcription factors are critical cancer drivers but have remained difficult to drug directly with small molecules; thus, alternative approaches to regulate MYC expression or activity are of high interest. We have previously demonstrated that MYC family members are regulated by YTHDC1. In AML cells, MYC mRNA is post-transcriptionally modified with methylation of adenosine at the N6 position (m6A), and m6A-marked MYC transcripts localize within phase-separated assemblies, termed biomolecular condensates, with the m6A reader, YTHDC1. YTHDC1 condensates regulate m6A-marked MYC and other oncogenic transcripts and promote cancer cell proliferation including in MYC-driven AML and small cell lung cancer (SCLC). Here, we describe the identification of YTHDC1 inhibitors optimized utilizing structure-based drug design (SBDD). This series of inhibitors occupies the RNA binding pocket of YTHDC1 and disrupts its interaction with m6A-RNA at nanomolar potencies in biochemical and cellular assays. The inhibitors are selective for YTHDC1 over other YTH family members and selectively dissolve YTHDC1 condensates over other condensate systems. Profiling in broader kinase and safety panels also suggests that these YTHDC1 inhibitors are selective with a favorable in vitro safety profile. Our lead molecule is drug-like, orally bioavailable, has suitable ADME properties and is well-tolerated in vivo. In MYC- and MYCL-driven AML and SCLC cells, respectively, we demonstrate the presence of YTHDC1 condensates, which are abrogated by YTHDC1 inhibition. Consistent with the genetic perturbation of YTHDC1, pharmacologic inhibition of YTHDC1 reduces MYC expression and results in anti-proliferative and pro-apoptotic phenotypes. Induction of myeloid differentiation markers is also observed in AML cells upon YTHDC1 inhibition. We evaluate the effects of YTHDC1 inhibition on primary patient AML samples. In addition, we demonstrated no impact on normal CD34+ progenitor cells. YTHDC1 inhibition results in in vivo efficacy at well-tolerated doses in multiple AML and SCLC xenograft models. Further, we demonstrate a dose-dependent PK/PD/efficacy relationship, suggesting on-target YTHDC1 activity through suppression of the MYC pathway. Thus, our data demonstrate that targeting YTHDC1 condensates represents a novel approach to the treatment of MYC-driven tumors. Citation Format: Richard C. Centore, Mark Charles, Mansi Arora, Marius Rebmann, Jerome Cattin, Xuejing Yang, Emily Batchelor, Matthew Watson, Nagakumar Bharatham, Prathima Radhakrishanan, Alex Howarth, Seema Qamar, Laura Andraghetti, Martin Kulander, Tuomas Knowles, Michael G. Kharas, Shilpi Arora. Discovery of potent, selective, and orally bioavailable small molecule inhibitors of YTHDC1 for the treatment of MYC-driven cancers [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 453.