Targeted protein degradation: current molecular targets, localization, and strategies

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Cell Biology

Background:

• Targeted protein degradation (TPD) has emerged as a powerful therapeutic modality.
• Initially focused on intracellular targets, TPD's scope has broadened significantly.
• The field has evolved over two decades, expanding beyond cancer therapeutics.

Purpose of the Study:

• To review the expanding landscape of targeted protein degradation.
• To highlight novel protein targets beyond traditional applications.
• To discuss strategies for targeting challenging protein locations like the extracellular matrix and membranes.

Main Methods:

• Comprehensive literature review of recent advancements in TPD.
• Analysis of TPD strategies applied to diverse protein targets.
• Examination of TPD applications in various disease contexts.

Main Results:

• TPD is increasingly applied to a wider range of proteins and diseases.
• Targeting extracellular matrix and membrane proteins presents new opportunities and challenges.
• Innovative TPD strategies are being developed for difficult-to-drug targets.

Conclusions:

• TPD holds immense potential for treating various diseases by targeting diverse proteins.
• Overcoming challenges in targeting extracellular and membrane proteins is crucial for future TPD development.
• This review provides insights into the evolving strategies and future directions in TPD for drug discovery.