Targeting the MYCN interaction network in neuroblastoma

Neuroblastoma is a common solid tumour in children and accounts for a disproportionate share of childhood cancer mortality. High-risk neuroblastoma is a major clinical challenge, with survival rates below 50% despite intensive therapy. Amplification of the MYCN oncogene is a hallmark of high-risk disease. MYCN protein is a transcription factor that promotes proliferation and blocks differentiation. MYCN is often described as ‘undruggable’ due to its lack of enzymatic activity and intrinsically disordered nature that means it lacks well-defined binding pockets for small molecules. This review explores the molecular interactome of MYCN as an opportunity for therapeutic discovery. We highlight functional and structural features of the interactions with key partners, such as MAX, WDR5, TFIIIC5 and Aurora kinase A. We discuss emerging strategies to disrupt MYCN interactions and to enable its degradation through disruption of protein stabilisation mechanisms or the use of degraders such as proteolysis targeting chimeras. By integrating knowledge of MYCN biology, molecular structures and chemical biology, these approaches provide promising routes towards targeted therapies for MYCN-driven neuroblastoma.