N-myc proto-oncogene protein (MYCN) (MYCN)

N-myc proto-oncogene protein (MYCN) is a transcription factor belonging to the MYC family, characterized by a basic helix-loop-helix leucine zipper (bHLH-LZ) domain. It plays a pivotal role during embryonic development, particularly in the expansion of progenitor cells in the central and peripheral nervous systems (UniProt P04198). In many pediatric and adult malignancies, MYCN is aberrantly expressed or amplified, most notably in high-risk neuroblastoma where it serves as a primary driver of oncogenesis and a poor prognostic indicator (NCBI Gene ID: 4613). MYCN functions by forming a heterodimer with the protein MAX to bind E-box sequences, thereby regulating the expression of genes involved in cell cycle progression, metabolism, and self-renewal. Although historically considered undruggable due to its disordered structure and lack of a traditional ligand-binding pocket, modern therapeutic approaches target the MYCN pathway through indirect means. These include inhibiting its transcription via BET or CDK inhibitors, promoting its degradation by disrupting its interaction with Aurora Kinase A, or using mini-proteins like Omomyc to disrupt its DNA-binding capabilities (PMID: 33806106).

Other names

N-mycNMYCNeuroblastoma-derived MYCbHLHe37Class E basic helix-loop-helix protein 37MODED

Inhibition of MYCN activity through multiple strategies: direct disruption of MYCN-MAX dimerization, transcriptional repression via BET bromodomain or CDK7/9 inhibition, and induction of protein degradation by disrupting the MYCN-Aurora Kinase A stabilizing complex (PMID: 33067305, 32819645).