Lessons learned in linking PROTACs from discovery to the clinic

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Targeted protein degradation offers superior efficacy over conventional inhibitors.
• It addresses previously undruggable targets, driving interest in novel modalities.
• Proteolysis targeting chimeras (PROTACs) are a key protein degradation modality.

Purpose of the Study:

• To review lessons learned in PROTAC optimization.
• To emphasize the linker region's role in PROTAC development.
• To discuss PROTACs' evolution into a clinical modality.

Main Methods:

• Review of preclinical data and clinical trial information.
• Analysis of PROTAC structure-activity relationships.
• Focus on linker properties and their impact.

Main Results:

• Linker optimization significantly impacts PROTAC pharmacology and metabolic fate.
• Physicochemical challenges, particularly oral bioavailability, are being addressed.
• PROTACs are transitioning from research tools to clinical therapeutics.

Conclusions:

• PROTAC technology is advancing rapidly, offering significant therapeutic promise.
• Understanding linker contributions is vital for successful PROTAC design.
• Clinical data provides valuable insights for future PROTAC development.