Targeted Protein Degradation: Current and Emerging Approaches for E3 Ligase Deconvolution

Area of Science:

• Biochemistry
• Drug Discovery
• Molecular Biology

Background:

• Targeted protein degradation (TPD) is an emerging therapeutic strategy using proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs).
• These molecules induce proximity between E3 ligases and proteins of interest (POIs), leading to POI degradation.
• A major limitation in TPD is the scarcity of known ligandable E3 ligases, with current efforts relying heavily on CUL4^CRBN and CUL2^VHL.

Purpose of the Study:

• To review and discuss current and emerging E3 ligase deconvolution approaches.
• To address the challenge of identifying novel ligandable E3 ligases for TPD.
• To highlight future directions for expanding the E3 ligase toolbox in TPD drug development.

Main Methods:

• Examination of established E3 ligase deconvolution techniques.
• Discussion of novel strategies for identifying E3 ligases from phenotypic screens.
• Analysis of approaches for target deconvolution in molecular glue degrader campaigns.

Main Results:

• Current methods for E3 ligase identification are often serendipitous or rely on phenotypic screening.
• Systematic deconvolution approaches are crucial for expanding the repertoire of ligandable E3 ligases.
• Advancements in deconvolution are needed to overcome the limitations of existing E3 ligases.

Conclusions:

• Expanding the landscape of ligandable E3 ligases is critical for advancing TPD therapies.
• Systematic deconvolution methods offer a promising path for discovering new E3 ligases.
• Future research should focus on developing and implementing robust deconvolution strategies to accelerate TPD drug discovery.