Therapeutic targeting of MYC- and MYCN-driven medulloblastoma with a novel MYC degrader molecule

Abstract

BackgroundMedulloblastoma (MB) is the most common malignant brain tumour in children, and aggressive subgroups are frequently driven by the oncoproteins MYC or MYCN. Direct therapeutic targeting of MYC/MYCN has been challenging because of their intrinsically disordered protein structures. The aim of this study was to determine whether novel SE486-11 analogues (UNSW-SCs) can therapeutically target MYC/MYCN-driven MB. MethodsThe anticancer activity of UNSW-SCs was assessed in MB cell lines with differential MYC/MYCN expression. Target engagement was evaluated using surface plasmon resonance and drug affinity responsive target stability assays. Blood-brain barrier penetration, MYC/MYCN protein degradation, cell cycle effects, apoptosis, DNA damage, and synergy with histone deacetylase (HDAC) inhibitors were examined. Therapeutic efficacy was evaluated in murine models of MYC- and MYCN-driven human MB. ResultsUNSW-SCs showed potent anticancer activity, with preferential selectivity toward MB cells expressing high MYC/MYCN levels and IC50 values ranging from 0.22 to 1.18 M. The lead molecule, UNSW-SC-22, directly bound MYC, crossed the blood-brain barrier, and achieved a brain-to-plasma ratio of 1.44 at peak concentrations. UNSW-SC-22 induced MYC/MYCN-dependent cytotoxicity associated with enhanced proteasomal degradation, cell cycle arrest, apoptosis, and DNA damage. Combined treatment with HDAC inhibitors further reduced MYC/MYCN protein levels, increased DNA damage, and enhanced apoptosis. In vivo, UNSW-SC-22, either alone or with entinostat, significantly suppressed intracranial tumour growth and prolonged survival. ConclusionsUNSW-SC-22 is a brain-penetrant MYC/MYCN-targeting molecule with potent preclinical activity in MYC/MYCN-driven MB, supporting its development as a monotherapy or combination strategy with HDAC inhibition. Key PointsO_LIUNSW-SC-22 directly targets MYC/MYCN in medulloblastoma. C_LIO_LIUNSW-SC-22 crosses the blood-brain barrier and prolongs survival. C_LIO_LIHDAC inhibition enhances UNSW-SC-22 activity in MYC-driven cells. C_LI Importance of the StudyMYC- and MYCN-driven medulloblastomas remain among the most aggressive paediatric brain tumours, yet direct pharmacological targeting of MYC/MYCN has historically been difficult. This study identifies UNSW-SC-22 as a novel brain-penetrant small molecule that directly engages MYC/MYCN and promotes proteasomal degradation, leading to tumour cell death. Compared with prior MYC-directed approaches, UNSW-SC-22 combines direct target engagement, blood-brain barrier penetration, and in vivo efficacy in orthotopic MYC- and MYCN-driven medulloblastoma models. The study further demonstrates that combining UNSW-SC-22 with histone deacetylase inhibition enhances MYC/MYCN suppression, DNA damage, apoptosis, and survival benefit. These findings provide a translational framework for developing MYC/MYCN degradation as a therapeutic strategy for high-risk medulloblastoma and support future pharmacological optimisation, biomarker-guided patient selection, and combination therapy development.