PROTACs: A novel strategy for cancer therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Small molecular inhibitors (SMIs) and monoclonal antibodies (mAbs) target specific proteins but struggle with intracellular, non-druggable targets.
• Proteolysis-Targeting Chimeras (PROTACs) have emerged as a powerful strategy to degrade proteins, including transcription factors and scaffold proteins.
• PROTACs utilize the cell's natural ubiquitin-proteasome system to eliminate target proteins.

Purpose of the Study:

• To review the historical development and future prospects of PROTAC technology.
• To highlight the evolution of PROTACs from peptide-based to small molecule-based and light-controllable systems.
• To discuss the diverse range of protein targets addressed by PROTACs in various diseases.

Main Methods:

• Review of scientific literature on PROTAC development and applications.
• Analysis of different generations of PROTACs, including their E3 ligase partners and target specificities.
• Discussion of challenges and advancements in PROTAC technology, such as cellular permeability, stability, and specificity.

Main Results:

• First-generation peptide-based PROTACs faced limitations in cellular permeability and stability.
• Second-generation small molecule-based PROTACs utilize various E3 ligases (MDM2, VHL, IAPs, Cereblon) and target oncogenic proteins (ER, AR, BRDs), fusion proteins (NPM/EML4-ALK, BCR-ABL), and mutant proteins (EGFR, kinases).
• Third-generation light-controllable PROTACs offer enhanced specificity and reduced toxicity by enabling light-triggered target degradation.

Conclusions:

• PROTACs represent a significant advancement in targeting previously undruggable proteins for therapeutic intervention.
• Light-controllable PROTACs provide a promising avenue for improving the safety and efficacy of targeted protein degradation.
• Further development of PROTACs holds great potential for future clinical applications in treating various diseases, particularly cancer.