Lessons from natural molecular glue degraders

Area of Science:

• Drug Discovery
• Molecular Biology
• Biochemistry

Background:

• Molecular glues (MGs) are emerging as a significant tool in drug discovery.
• Unlike bivalent proteolysis targeting chimeras (PROTACs), monovalent MGs can induce degradation of previously non-ligandable proteins.
• MGs function by enhancing the interaction between proteins and E3 ubiquitin ligases, facilitating targeted protein degradation.

Purpose of the Study:

• Analyze characteristics of natural MG degraders.
• Contrast natural MGs with synthetic MGs.
• Provide a rationale for optimizing MG design for therapeutic applications.

Main Methods:

• Comparative analysis of natural and synthetic MG degradation mechanisms.
• Affinity assessment of MG-E3 ligase and MG-substrate interactions.
• Review of existing synthetic MGs like immunomodulatory drugs (IMiDs) and CR8.

Main Results:

• Natural MGs form transient ternary complexes, with weak affinities between individual components.
• Synthetic MGs, such as IMiDs and CR8, often exhibit potent inhibitory activity against their target E3 ligases or associated kinases.
• Natural MG systems show dissociation after substrate degradation due to low micromolar affinities.

Conclusions:

• Optimizing synthetic MGs by reducing their affinity to E3 ligases can yield degraders without inhibitory activity.
• Weakening interactions, like CR8-CDK, can decouple degrader function from kinase inhibition.
• Future MG degrader development should aim to mimic natural systems, reducing off-target effects and side effects by avoiding inherent inhibitory activity.