Monte Rosa Therapeutics

What is a Molecular Glue Degrader?

Many diseases stem from abnormal protein function. Traditional small molecule inhibitor drugs fall short, leaving approximately 85% of proteins undruggable.
Enter Molecular Glue Degraders (MGDs). We rationally design MGDs which take us beyond these limitations, reprogramming the cell’s natural protein degradation system to selectively degrade and eliminate hard to target proteins.

MGDs:

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Are clinically validated

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Have favorable drug-like properties

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Can achieve unprecedented target selectivity

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Can access differentiated, novel target space

How glues work

MDGs function by binding to an E3 ligase, such as cereblon, creating a neosurface.

The MGD E3-ligase neosurface engages structural features on the surface of the target protein.

The E3 ligase marks the target protein for degradation by attaching a molecular tag known as ubiquitin. The MGD-E3 ligase can then tag more target proteins for degradation.

Proteasomes then degrade the ubiquinated the target protein, permanently eliminating it.

Novel binding modes

By rationally expanding the diversity of our MGDs, we’re able to degrade more proteins, expanding from those with known surface features to those with surfaces never before engaged. This breakthrough allows us to target a wider range of therapeutically relevant proteins.

Canonical surfaces

Novel surface example

Novel surface example

Quantitative and Engineered Elimination of Neosubstrates (QuEEN™)

The QuEEN™ discovery engine, powered by AI/ML, works at the interface of technology (machine learning, chemistry, biology, and automation) and life sciences to rewrite drug discovery. Using QuEEN, we've made exquisitely selective, long duration, catalytic MGDs that deeply modulate disease pathways.

  • Proprietary MGD library

    Library of novel, diverse MGDs with drug-like properties enabling a broad exploration of target space

  • high throughput screening

    High throughput screening of our proprietary library identifies active MGDs

  • Proteomics Engine

    An integrated engine that detects novel targets and ensures MGD selectivity through proprietary proteomic assays

  • STRUCTURE-BASED DESIGN

    Expanding repository of cryo-EM and crystal structures that enable rational MGD optimization

Anchored by data, powered by AI

Using geometric deep learning to identify targets, protein surfaces to match targets to ligases, and virtual screening to design MGDs, our integrated data moat and AI algorithms guide our drug discovery.

Our groundbreaking approach goes beyond existing targets to degrade proteins once considered undruggable.

With QuEEN™, we've rationally designed highly potent and selective MGDs that degrade disease-causing proteins. Our MGDs uniquely reshape the surface of the E3 ligase, enabling engagement with proteins through vastly different binding modes, extending far beyond established degron surfaces. Our understanding and utilization of novel binding modes allows us to fine-tune selectivity and broadens our target space to treat more diseases.

Pipeline

Our QuEEN discovery engine has delivered oral MGDs that selectively degrade high-potential, hard-to-drug proteins, offering new treatment possibilities for cancer, autoimmune, inflammatory, and other diseases.

View Pipeline