Protacs

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that induce selective degradation of intracellular proteins. A PROTAC binds a target protein with one ligand and an E3 ubiquitin ligase with another ligand, joined by a linker. This proximity forces ubiquitination of the target by the ligase and its subsequent destruction by the proteasome. Because the PROTAC can act catalytically, a single molecule may trigger degradation of many target molecules.

Design and components: A PROTAC comprises a target-binding ligand, an E3 ligase–binding ligand, and a linker. Common E3 ligases used in PROTACs include VHL and Cereblon. The choice of ligases, binding affinity, and linker length and rigidity influence the efficiency and selectivity of degradation. Due to their size, PROTACs require careful optimization for cellular uptake, stability, and in vivo pharmacokinetics.

Applications and status: PROTACs aim to degrade proteins that are difficult to inhibit with conventional drugs, such as certain transcription factors. They are being investigated primarily in cancer, with ongoing research in neurodegenerative and other diseases. A number of PROTACs have entered clinical trials, demonstrating target engagement and antitumor activity in some cases. Their therapeutic advantages include catalytic action and potential to overcome resistance to inhibitors.

Limitations and challenges: Major hurdles include achieving favorable pharmacokinetic properties, avoiding off-target degradation, and preventing resistance through mutations in the target or E3 ligase. Ongoing research seeks to expand E3 ligase options, improve selectivity, and develop safer, more tissue-specific PROTACs.