Targeted Protein Degradation: New Horizons in Medicinal Chemistry Tools

Targeted protein degradation (TPD) has emerged as a transformative strategy in modern medicinal chemistry, expanding the frontiers of drug discovery. By moving beyond traditional occupancy-driven pharmacology, TPD harnesses the cell's intrinsic proteostasis mechanisms—namely the ubiquitin-proteasome system and lysosomal degradation pathways—to selectively eliminate disease-associated proteins. Key innovations include PROTACs, TRAFTACs, dual PROTACs, and PROTABs, each leveraging event-driven mechanisms to catalytically degrade target proteins with enhanced selectivity and reduced dosing requirements. Molecular glue degraders and tag-based degron systems further diversify the TPD toolkit, enabling the modulation of previously “undruggable” targets. Meanwhile, advances like LYTACs and CIDEs open new avenues for degrading extracellular and membrane proteins. These evolving chemical modalities promise superior therapeutic potential, especially in oncology, by overcoming drug resistance and enhancing pharmacological precision. As over 20 TPD-based therapeutics have entered clinical trials, the approach stands as a promising modern medicinal chemistry tool.