Targeted Degradation of the c-Myc Oncoprotein: Molecular Mechanisms, Technological Platforms, and Therapeutic Perspectives in Oncology

Background/Objectives: The c-Myc oncoprotein is a master regulator of cell cycle progression, cellular metabolism, and ribosome biogenesis, and its dysregulation occurs in more than 70% of human malignancies. Its intrinsically disordered structure and absence of deep hydrophobic binding pockets have historically limited direct pharmacological targeting, leading to its classification as an “undruggable” protein. Targeted protein degradation offers strategies to reduce c-Myc abundance by recruiting endogenous degradation machinery or introducing an exogenous protease. Methods/Results: This review evaluates recent strategies for reducing c-Myc abundance—classified into direct c-Myc degraders, indirect destabilization pathways, and proposed platform adaptations—encompassing established small-molecule modalities, including heterobifunctional proteolysis-targeting chimeras (PROTACs) and molecular glues, oligonucleotide-based PROTACs, proteomimetic polymers, MIDN-dependent ubiquitin-independent proteasomal degraders, and orthogonal bacterial proteases. Adaptable platforms, including KRAS-directed TKD constructs and anti-c-Myc modular nanotransporters (MNTs), are discussed separately because c-Myc degradation has not yet been demonstrated for these adaptations. Conclusions: Collectively, these approaches broaden the potential of c-Myc-targeted degradation to address therapeutic resistance, influence the tumor immune microenvironment, and facilitate the clinical translation of intranuclear degraders.