Primed for degradation: How weak protein interactions enable molecular glue degraders

Area of Science:

• Biochemistry
• Drug Discovery
• Molecular Biology

Background:

• Molecular glues are small molecules that induce or enhance protein-protein interactions.
• These interactions can lead to ubiquitination by proximity, particularly with ubiquitin ligases.
• Rational design of molecular glues is a significant challenge in drug development.

Purpose of the Study:

• To review recent insights into molecular glues.
• To discuss emerging design principles for molecular glues and mutations.
• To present a thermodynamic model for rationalizing molecular glue action.

Main Methods:

• Literature review of molecular glues and protein-protein interactions.
• Analysis of design principles for small molecules and mutations.
• Development of a thermodynamic model for molecular glue action.

Main Results:

• Molecular glues can induce de novo or facilitate weak protein-protein interactions.
• Mutations or compounds can complement protein surfaces, leading to gain of function.
• Compounds must provide significant binding energy for small or weak interaction surfaces.

Conclusions:

• Emerging design principles are guiding the development of molecular glues.
• A thermodynamic model can rationalize the action of compounds and mutations in protein binding.
• Molecular glues represent a transformative modality with potential in drug discovery.