Basic Introduction

Proteolysis-Targeting Chimeras (PROTACs) represent a novel drug design strategy. The principle includes a PROTAC molecule that simultaneously binds a target protein (Protein of Interest, POI) and an E3 ubiquitin ligase, forming a ternary complex. This brings the POI into proximity with the E3 ligase, leading to ubiquitination of the target protein. The ubiquitinated POI is then recognized and degraded by the 26S proteasome, effectively eliminating its biological function. PROTAC technology overcomes the limitations of traditional small-molecule inhibitors, especially for undruggable targets such as transcription factors, nuclear proteins, and scaffold proteins, with considerable potential for new drug discovery.

Technical Principle

A PROTAC molecule consists of two functional ligands joined by a chemical linker: one end specifically binds the target protein (POI ligand), while the other binds an E3 ubiquitin ligase (E3 ligase ligand). When both ends are engaged, a ternary complex is formed (POI–PROTAC–E3 ligase), enabling the E3 ligase to ubiquitinate the POI. The ubiquitinated protein is subsequently recognized by the cellular 26S proteasome and degraded. Through this process, the biological activity of the target protein is effectively inhibited.

The mechanism of PROTAC 1

Applications and Technical Advantages

1. Degrading “Undruggable” Targets

PROTACs offer a highly effective, selective, and efficient method to eliminate target proteins. Unlike traditional inhibitors, PROTACs do not need to bind functional domains of proteins or exhibit high binding affinity. They can recognize non-functional regions of the target protein, making it possible to degrade many targets previously considered “undruggable.”

2. Targeting Multifunctional Proteins

As degraders, PROTACs can eliminate the entire function of a target protein, providing an advantage over small-molecule inhibitors that only block specific active sites. This feature is highly beneficial for complex or multifunctional therapeutic targets.

3. Overcoming Drug Resistance

By promoting degradation of the target protein rather than inhibiting its activity, PROTACs can circumvent common drug resistance mechanisms, such as target overexpression or mutation, which often limit the efficacy of traditional small molecules.