Abstract Background Deregulated MYC signalling is a central oncogenic driver in high-risk medulloblastoma (MB) and diffuse intrinsic pontine glioma (DIPG), where it promotes aggressive tumour growth and treatment resistance. Somatic H3K27M mutations occur in DIPG tumours and drive epigenetic reprogramming that sustains oncogenic transcriptional programs, including MYC and MYCN signalling. Methods We developed a series of small-molecule MYC inhibitors (UNSW-SC compounds) derived from the lead scaffold SE486-11 (Cheung, Oncogene, 2021), with improved potency. The lead compound, UNSW-SC-22, was evaluated in MYC-driven MB and DIPG models using pharmacology, genetic dependency assays, target-engagement studies (SPR and CETSA), transcriptomic profiling, and in vivo efficacy studies in orthotopic and transgenic mouse models. Results UNSW-SC-22 demonstrated potent and selective cytotoxicity in MYC-high MB and DIPG cells (IC50: 0.02-2.6 μM) and a wide therapeutic index. Sensitivity correlated strongly with MYC expression levels, confirming MYC- and MYCN-dependent activity. Mechanistically, UNSW-SC-22 directly bound full-length c-MYC and MYCN, reduced their protein half-life by approximately two-fold, and promoted phosphorylation-dependent proteasomal degradation without affecting MYC mRNA levels. Transcriptomic analyses revealed suppression of MYC-regulated and activation of p53-associated stress responses. Most importantly, UNSW-SC-22 effetely crossed the blood–brain barrier, achieving brain concentrations exceeding in vitro IC50 values (brain Cmax 10.8 μM), and showed a favourable in vitro safety pharmacology profile. In vivo, UNSW-SC-22 significantly reduced tumour burden and prolonged survival in MYCN-driven MB transgenic (p = 0.0004) and orthotopic xenografts models. In orthotopic DIPG models, SC-22 significantly reduces tumour burden, extends median survival by 10.5 days. UNSW-SC-22 synergised with clinically relevant histone deacetylase inhibitor, Entinostat, resulting in survival benefit compared with either agent alone. Conclusions These findings establish MYC as a therapeutically actionable vulnerability in lethal childhood brain tumours and support dual targeting of MYC and epigenetic regulators as a promising strategy for high-risk MB and incurable DIPG.
Cheung et al. (Tue,) studied this question.