Vol. 8, Issue 1, Part A (2026)

PROTACs (Proteolysis-Targeting Chimeras) and Molecular Glues are thoroughgoing small molecules that confiscate the cell's ubiquitin-proteasome system (UPS) to demean disease-causing "undruggable" proteins, opening new approach for cancer and other treatments. PROTACs are bifunctional degraders (ligand-linker-E3 ligase binder) with reasonable design, molecular glues (monovalent) persuade new PPIs, frequently discovered fortunately but progressively reasonably, with superior drug-like properties like oral bioavailability, both working by generating a ternary complex for protein demolition, with proceeding research focusing on linker optimization, AI-driven design, and get the better of restraints like the "hook effect" for superior clinical success. 

Molecular Glues are small molecules with low molecular weight that proceed as a molecular bridge, ease interaction between a target protein and an E3 ubiquitin ligase to permit degradation without necessary classical binding pockets. PROTACs are heterobifunctional small molecules that concurrently captivate a target protein and an E3 ligase to persuade particular degradation through a catalytic mechanism. Both approach have extremely expanded the druggable proteome and carry considerable assurance for therapeutic interventions.

In cellular protein-degrading systems, K11, K48, and K63 included in ubiquitin linkages can act as degradative labels, namely K11 and K48 for proteasomal pathway and K63 for lysosomal pathway. The ubiquitination process, a step-wise enzymatic cascade involving ubiquitin activation, ubiquitin conjugation and ubiquitin ligation, includes all types of ubiquitinating enzymes.

This review furnishes a relative outline of Molecular Glues and PROTACs, involving their mechanisms, advantages and design principles.