PROTACs and Molecular Glues
PROTACs and molecular glues represent a class of small-molecule therapeutics with a revolutionary mode of action. They function by recruiting intracellular target proteins to E3 ubiquitin ligases, thereby promoting the ubiquitination of the targets and their subsequent degradation via the proteasome. This approach surpasses the conventional paradigm of merely inhibiting protein function, enabling direct elimination of disease-associated proteins and offering a novel strategy for addressing previously “undruggable” targets. The term PROTACs stands for Proteolysis Targeting Chimeras, referring to bifunctional small molecules typically comprising three components: a ligand that binds the target protein, a ligand that engages the E3 ubiquitin ligase, and a chemical linker connecting the two. Through the coordinated action of these elements, PROTACs and molecular glues facilitate the formation of a ternary complex between the target and the E3 ligase, which triggers ubiquitination and proteasomal degradation of the target protein. In contrast to traditional targeted therapeutics, PROTACs and molecular glues do not require continuous occupancy of the binding site to exert their function. This mechanism not only enhances pharmacological efficacy but also allows for reduced dosage and minimizes the development of drug resistance, thereby opening new avenues for targeted therapy. In recent years, PROTACs and molecular glues have attracted substantial attention from both basic research and drug discovery communities due to their high potency and broad applicability. Promising outcomes have been demonstrated across diverse disease areas, particularly in oncology, immune-related disorders, and neurodegenerative diseases. By enabling specific degradation of pathological proteins, this strategy provides a more complete functional blockade and circumvents treatment failures arising from mutations or acquired resistance.
At the molecular level, the functionality of PROTACs and molecular glues relies on hijacking the ubiquitin-proteasome system to selectively degrade proteins of interest. In cells, protein degradation is primarily mediated by this pathway, wherein proteins modified with ubiquitin tags are recognized and eliminated by the proteasome. PROTACs and molecular glues initiate this endogenous degradation process by inducing proximity between the target protein and an E3 ligase. The overall degradation efficiency is influenced by several factors, including the presence of a ligandable site on the target protein surface, the expression level of the E3 ligase in specific cell types, and the stability and conformational compatibility of the resulting ternary complex. Among the widely used E3 ligases are CRBN (Cereblon) and VHL (von Hippel–Lindau). Notably, PROTACs and molecular glues have demonstrated significant activity against traditionally “undruggable” targets such as transcription factors and protein–protein interaction (PPI) interfaces, thus markedly expanding the scope of therapeutic intervention.
Although the term "molecular glue" is widely used to describe PROTACs and related compounds, it primarily reflects their functional role in mediating interactions between target proteins and E3 ligases, rather than denoting a literal glue-like molecular structure. In a strict sense, PROTACs are rationally designed chimeric molecules with defined binding elements, where the induced association is achieved through molecular recognition and spatial complementarity. Consequently, the design of PROTACs and molecular glues requires meticulous optimization, including the selection of suitable ligands for both the target protein and the E3 ligase, as well as fine-tuning the length, flexibility, and chemical properties of the linker. A linker that is too short may constrain molecular dynamics and hinder ternary complex formation, while an excessively long linker may introduce unnecessary instability. Furthermore, properties such as polarity, flexibility, and solubility of the linker critically influence the compound’s cellular permeability and in vivo pharmacokinetics.
The advantages of PROTACs and molecular glues extend beyond their degradation-based mechanism. Notably, they can maintain sustained pharmacological effects even at low doses due to their catalytic mode of action: a single PROTAC molecule can repeatedly induce the degradation of multiple target protein molecules without requiring persistent binding. This not only enhances therapeutic efficiency but also reduces the risk of off-target toxicity commonly observed with traditional inhibitors. Nonetheless, several technical challenges remain. The relatively high molecular weight of PROTACs and molecular glues may lead to poor oral bioavailability. Additionally, cell-type-specific differences in E3 ligase expression can limit their universality and therapeutic breadth. Some PROTAC compounds also exhibit restricted tissue penetration and limited membrane permeability, which necessitate further refinement during compound optimization and preclinical development.
MtoZ Biolabs provides comprehensive, one-stop research services encompassing target identification, quantitative protein analysis, and functional validation. Our advanced proteomics platform delivers high-resolution, highly reproducible data to support research on disease-relevant proteins, accelerating drug discovery and deepening mechanistic understanding at the molecular level.
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