A Small Molecule Selectively Targets N-Myc to Suppress Neuroblastoma Cancer Progression.

Neuroblastoma, a prevalent and lethal extracranial solid tumor in childhood, remains a significant challenge in pediatric oncology worldwide. High-risk neuroblastoma (HR-NB) is particularly aggressive and linked to a poor prognosis due to the limited availability of effective treatments. The aberrant amplification of the MYCN gene is a critical genetic alteration observed in neuroblastoma conferring poorer clinical outcomes. To date, no drugs targeting N-Myc have been approved. In this study, we successfully established a novel high-throughput screening system targeting N-Myc and identified the first small molecule inhibitor, N78, which exhibits selective, high affinity for N-Myc over c-Myc. N78 selectively degrades N-Myc, suppresses the expression of its target genes, and effectively diminishes the viability of MYCN-dependent tumor cells. Notably, N78 demonstrates acceptable tolerability and induces significantly enhanced tumor regression in vivo compared to Myci975, a leading candidate among c-Myc/N-Myc inhibitors. Mechanistically, N78 promotes the phosphorylation of N-Myc at threonine-58, leading to its degradation via the ubiquitin-proteasomal pathway. This study presents the first selective N-Myc inhibitor N78, and highlights the promise of small-molecule N-Myc inhibitors as both chemical probes and potential anti-cancer therapies for neuroblastoma.