Molecular glues and PROTACs in targeted protein degradation: mechanisms, advances, and therapeutic potential

Abstract

Targeted protein degradation (TPD) is a transformative approach to drug discovery that enables the modulation of proteins previously considered "undruggable." Unlike traditional inhibitors, which transiently suppress protein activity, TPD harnesses the ubiquitin-proteasome system to selectively eliminate specific proteins and thereby fully abolish their activities. Two prominent approaches within TPD, Molecular Glues and PROteolysis TArgeting Chimeras (PROTACs), differ in both mechanism and therapeutic application. Molecular Glues are small molecules with low molecular weight that act as a molecular bridge, facilitating interaction between a target protein and an E3 ubiquitin ligase to enable degradation without requiring classical binding pockets. PROTACs are heterobifunctional small molecules that simultaneously engage a target protein and an E3 ligase to induce selective degradation through a catalytic mechanism. Both strategies have vastly expanded the druggable proteome and hold great promise for therapeutic interventions. This review provides a comparative overview of Molecular Glues and PROTACs, including their mechanisms, design principles, and therapeutic applications. We highlight their physicochemical properties, advantages, and limitations, as well as recent advances that are fueling the discovery of novel degraders. Through clinical advancements and case studies, we examine how these modalities are reshaping drug discovery and enabling new treatments for a variety of diseases.

Keywords: Chemical biology; Drug discovery; Molecular glues; PROTACs; Targeted protein degradation; Ubiquitin-proteasome system.