Protein degraders - from thalidomide to new PROTACs

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Protein degraders are a rapidly advancing class of therapeutic compounds.
• Two main types exist: proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs).
• The mechanism of action for thalidomide, an MGD, has been elucidated, identifying cereblon (CRBN) as its target.

Purpose of the Study:

• To provide a historical overview of protein degrader development.
• To highlight key milestones from thalidomide to modern PROTACs and MGDs.
• To discuss the impact of protein degraders on therapeutic and basic biological research.

Main Methods:

• Literature review of historical and recent developments in protein degrader research.
• Analysis of the molecular mechanisms and clinical applications of PROTACs and MGDs.
• Discussion of emerging technologies and future directions in the field.

Main Results:

• Thalidomide, a well-known MGD, paved the way for understanding CRBN-mediated degradation.
• Several CRBN-binding MGDs (thalidomide, lenalidomide, pomalidomide) are approved for treating diseases like multiple myeloma.
• Numerous PROTACs and MGDs are in clinical trials, demonstrating broad therapeutic potential.

Conclusions:

• Protein degraders represent a significant advancement in drug discovery and development.
• The historical progression from thalidomide to advanced PROTACs showcases remarkable scientific achievement.
• These compounds offer new avenues for treating intractable diseases and advancing biological understanding.