Abstract 6863: Development of MYCN/MYC inhibitors

Abstract Background: Deregulated expression of MYC family transcription factors is present in more than 70% of human cancers. MYC is an intrinsically disordered protein without known drug binding pockets and is essential for adult cell replication, making clinical development of MYC inhibitors challenging. MYCN amplification and overexpression generate driver signals in the childhood cancers, neuroblastoma (NB), medulloblastoma (MB) and diffuse intrinsic pontine glioma (DIPG). Methods and Results: We previously reported a small molecule compound, SE486-11, which reduced MYCN protein levels in combination with suberoylanilide hydroxamic acid. We developed more potent analogues of SE486-11 with improved single agent potency, selectivity towards cancer cells and solubility (UNSW-SC compounds). Our lead compound, UNSW-SC-22 is highly effective in vitro against MYCN-driven NB and MB cells with sub-micromolar IC50 values and displayed a wide therapeutic index. UNSW-SC-22 displayed MYCN- and c-MYC-dependent cytotoxicity and decreased MYCN and c-MYC protein levels in NB and MB cell lines. MYCN and c-MYC protein half-life was decreased ∼2-fold, while K-48-linked ubiquitination of MYCN protein was increased by UNSW-SC-22. We show UNSW-SC-22 bound to full length MYCN and c-MYC proteins directly, with KDs of 62.7 µM and 60.5 µM, respectively, by surface plasmon resonance. In-cell target engagement was further confirmed by drug affinity responsive target stability and cellular thermal shift assays. Total RNA from NB and MB cells treated with UNSW-SC-22 showed down-regulation of MYC target genes on GSEA analyses. On in-vitro pharmacology profiling against 47 intracellular signalling targets (78 assays) known to cause adverse drug reactions in humans, UNSW-SC-22 demonstrated no significant target activation at <20 µM. UNSW-SC-22 freely crossed the blood-brain barrier, reaching a concentration of 10.8 µM in brain tissue, with a half-life of 1.22 hours. UNSW-SC-22 significantly reduced the tumour burden and improved overall survival of MYCN-driven NB and MB mice. MYCN protein expression was downregulated in tumours collected from mice treated with UNSW-SC-22. Conclusion: Collectively, our data suggest that MYCN and c-MYC are the direct molecular targets of UNSW-SC compounds. These compounds have strong potential to serve as specific targeted therapy to treat MYCN/c-MYC driven paediatric and adult cancers. Citation Format: Satyanarayana Gadde, Sin Wi Ng, Natalie Chung, Qian Wang, Larissa Doughty, Tracey Nero, Maria Tsoli, David Ziegler, Louis Chesler, Michael Parker, Naresh Kumar, Belamy Cheung, Glenn Marshall. Development of MYCN/MYC inhibitors [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 6863.