Routes to molecular glue degrader discovery

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Molecular glue degraders (MGDs) are an emerging class of targeted protein degradation (TPD) therapeutics.
• They function by inducing interactions between E3 ubiquitin ligases and specific neo-substrates.
• This mechanism enables the targeting of proteins previously considered undruggable or poorly targetable.

Purpose of the Study:

• To provide an overview of recently discovered MGDs and their varied mechanisms.
• To discuss strategies for the rational discovery of novel MGDs and neo-substrates.
• To highlight the potential of MGDs in expanding therapeutic options.

Main Methods:

• Review of recently reported MGDs and their mechanisms of action.
• Discussion of mechanism-based discovery strategies.
• Exploration of repurposing existing ligands, screening for novel binders, and utilizing functional genomics and proteomics.

Main Results:

• MGDs demonstrate diverse mechanisms for inducing targeted protein degradation.
• Several strategies are effective for discovering new MGDs and identifying neo-substrates.
• Functional genomics and quantitative proteomics are valuable tools for understanding MGDs.

Conclusions:

• MGDs represent a powerful and versatile TPD modality.
• Rational design approaches are advancing the field of MGD discovery.
• MGDs hold significant promise for targeting challenging disease-causing proteins.