This week, we have an in-depth conversation on molecular glue degradation, with Monte Rosa Therapeutics’ chief data and information officer John Castle.

Interview time:

03:52 Monte Rosa Therapeutics

Molecular glue degradation

A recent cover article in Science showcased research that expands by more than 1,000 the number of therapeutic targets (including undruggables) accessible through a protein degradation approach known as molecular glue degradation.

Using proprietary AI and ML approaches, researchers from Monte Rosa Therapeutics used algorithms to identify more than 1,600 human proteins predicted to be compatible with cereblon (a protein with a central role in cellular protein degradation) binding.

This allowed them to fingerprint previously unrecognised surfaces capable of recruiting cereblon for targeted protein degradation. These proteins represent more than 100 different target classes and a broad range of protein domains.

The techniques and know-how that enabled these discoveries will substantially expand the scope of disease-associated proteins their platform can address, including many targets historically considered undruggable. Their pipeline is proof they can address these undruggable targets, which has been the long-heralded promise of protein degradation.

Molecular glue degraders (MGD) are a type of protein degrader but have additional beneficial properties and the potential to treat many diseases that other modalities, including other degraders, cannot.

They are a class of small molecules that promote the degradation of specific proteins by “gluing” them to E3 ubiquitin ligases, leading to their ubiquitination and subsequent degradation by the proteasome.

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