Decoding MYC Targeted Inhibition in Cancer: Integrating Medicinal Insights With Computational Design Approaches

ABSTRACT The MYC family of oncoproteins, a central regulator of cellular proliferation and metabolism, is aberrantly regulated in over 70% of human cancers, making them a significant target for therapeutic intervention. Yet, MYC intrinsically disordered conformation and exclusive nuclear localisation have led to its popularity as ‘undruggable’. This review provides an in‐depth evaluation of the structure–activity relationship (SAR) of diverse small‐molecule inhibitors designed to target the undruggable MYC. We highlighted a spectrum of chemical scaffolds, including indenoisoquinoline, dibenzoquinoxaline, isaindigotone, quindoline, berberine and iminobenzimidazole derivatives and many others. The described inhibitors act by two primary mechanisms: disrupting the essential MYC‐MAX dimerisation and stabilising the c‐Myc promoter G‐quadruplex (G4) to suppress MYC transcription. Key SAR insights highlight the critical contributions in distinct structural motifs, including planar aromatic cores for π–π stacking, cationic side chains for electrostatic interactions and precisely positioned electron‐donating or electron‐withdrawing groups that determine inhibitory potency and selectivity. In silico docking studies highlighted the key interactions of the corresponding ligand molecules with the amino acid residues present within the active pocket of the MYC target. By systematically correlating chemical structure with biological activity across multiple classes through SAR and computational studies, this review establishes a robust framework to guide the rational development of next‐generation MYC inhibitors with enhanced clinical potential.