From Undruggable to Actionable: Redefining Druggability Through Emerging Therapeutic Modalities.

The concept of "undruggable" targets has long represented a major limitation in medicinal chemistry, referring to proteins and biomolecules that lack well-defined binding pockets or exhibit highly dynamic conformational behavior. However, advances in structural biology, chemical biology, and computational methodologies are rapidly expanding the scope of tractable therapeutic space. Emerging modalities, including targeted protein degradation, molecular glues, macrocycles, RNA-targeting small molecules, covalent ligands, and artificial intelligence-assisted molecular design, enable pharmacological mechanisms beyond classical occupancy-based inhibition through strategies such as induced proximity, expanded molecular recognition, covalent engagement, and RNA-level regulation. These approaches challenge the traditional binary classification of druggability and support a more context-dependent view of therapeutic accessibility. Despite this progress, significant challenges remain in optimizing pharmacokinetic properties, ensuring selectivity, minimizing toxicity, and achieving robust clinical translation. This editorial provides a mechanistic perspective on how emerging modalities are extending the boundaries of modern drug discovery.