AI Insight
Researchers developed UNSW-SC-22, a novel small molecule that can cross the blood-brain barrier and selectively degrade MYC and MYCN oncoproteins, which drive aggressive forms of medulloblastoma, the most common malignant brain tumor in children. The compound demonstrated potent anticancer activity in laboratory studies, with effectiveness enhanced when combined with histone deacetylase inhibitors, and significantly reduced tumor growth and extended survival in mouse models of MYC/MYCN-driven medulloblastoma. This represents a potential breakthrough in directly targeting MYC/MYCN proteins, which have historically been difficult to inhibit due to their disordered protein structures.
Why it matters
This research offers a promising new therapeutic approach for children with aggressive medulloblastoma subtypes that currently have limited treatment options and poor prognoses. The brain-penetrant properties of UNSW-SC-22 and its ability to target previously "undruggable" MYC/MYCN proteins could potentially improve survival outcomes and reduce treatment-related toxicities in pediatric brain cancer patients.
Understand the Science
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Medulloblastoma (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. Methods: The 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. Results: UNSW-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. Conclusions: UNSW-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.
Source: Therapeutic targeting of MYC- and MYCN-driven medulloblastoma with a novel MYC degrader molecule