Targeting “undruggable” cancer proteins: pharmacological challenges and emerging strategies

Precision oncology has revolutionized cancer biology, yet a critical disconnect persists: many pivotal oncogenic drivers, such as MYC, KRAS, and transcription factors, remain ‘undruggable’ by conventional small molecules due to a lack of traditional ligand-binding pockets. Overcoming this barrier is an urgent clinical necessity. This review maps and analyzes six key innovative strategies that are redefining druggability: (I) targeted protein degradation [TPD; proteolysis-targeting chimeras (PROTACs) and molecular glues], which catalytically eliminates proteins via the ubiquitin-proteasome system; (II) protein-protein interaction (PPI) inhibitors, which block critical oncogenic interfaces; (III) nucleic acid-based therapies [small interfering RNA (siRNA), antisense oligonucleotides (ASOs), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)], which modulate targets at the RNA or DNA level; (IV) covalent inhibitors, which form irreversible bonds with specific residues; (V) allosteric modulation, which exploits hidden or cryptic binding pockets; and (VI) artificial intelligence (AI), which accelerates discovery by predicting structures and designing novel molecules. For each modality, we discuss mechanistic principles, historical development, and clinical translation, highlighting success stories and persistent challenges. Finally, we synthesize these approaches into an integrated perspective, arguing that their future convergence, for example, using AI to design next-generation degraders or combining PPI inhibitors with immunotherapies, will be essential to overcome the limitations of any single approach and reshape the standard of care. This review argues that the paradigm of undruggability is being dismantled by a shift from simple occupancy-based inhibition to event-driven degradation, state-specific modulation, and root-cause genetic correction.