Chasing molecular glue degraders: screening approaches.

Area of Science:

• Biochemistry and Pharmacology
• Drug Discovery and Development

Background:

• Protein-protein interactions (PPIs) are fundamental to all biological processes.
• Small molecules can modulate PPIs by inducing proximity, leading to targeted protein degradation.
• Molecular glue degraders and proteolysis-targeting chimeras (PROTACs) represent advanced strategies beyond traditional occupancy-based therapeutics.

Purpose of the Study:

• To provide an overview of the molecular glue concept, focusing on E3 ligase proximity inducers.
• To highlight serendipitous and intentional discoveries of molecular glue degraders.
• To discuss screening strategies and future perspectives in this field.

Main Methods:

• Review of existing literature on molecular glue degraders and targeted protein degradation.
• Analysis of screening strategies for identifying novel molecular glue compounds.
• Discussion of the mechanism of action involving E3 ubiquitin ligases and proteasomal degradation.

Main Results:

• Molecular glue degraders are monovalent compounds that recruit target proteins to E3 ligases for degradation.
• Both natural and synthetic inducers of proximity to E3s are discussed.
• Examples of serendipitous and intentional discoveries of clinical and preclinical molecular glue degraders are presented.

Conclusions:

• Molecular glue degraders offer a powerful strategy to overcome limitations of traditional therapeutics.
• This approach enables the degradation of previously unligandable proteins, expanding the targetable proteome.
• Mastering the modulation of PPIs via molecular glues presents an exciting future for drug discovery.