Targeted protein degradation
Targeting previously “undruggable” targets
Targeted protein degradation is revolutionising therapeutics, unlocking the potential for new drugs for conditions that have previously been untreatable.
We’re building our expertise in this rapidly expanding field and the capability of our targeted protein degradation platform.
We’re interested in exploring collaborations to evolve this area further.
Our areas of focus
Our current focus is on proteolysis targeting chimeras – or PROTACs – and E3 ligases to increase options for targeted protein degradation approaches in different tissues and diseases.
E3 ligases
E3 ligases are a large family of enzymes that help to regulate the level of all intracellular proteins. They catalyse ubiquitination, a key step in the process where target proteins are tagged with ubiquitin, triggering their destruction by a cellular waste disposal system.
E3 ligases can be brought into close proximity to the target protein by a PROTAC molecule or a so-called molecular glue.
PROTACS
Proteolysis targeting chimeras (PROTACs) are the bifunctional small molecules that bring an E3 ligase close to the target protein for ubiquitination.
A single PROTAC molecule can do this step many times, meaning therapeutic doses can potentially be lower than for conventional antagonistic inhibitors.
Often larger and more complex than traditional small molecule compounds, PROTACS typically require different strategies for their design, chemical synthesis and characterisation assays.
What is targeted protein degradation (TPD)?
Small molecules – like aspirin, some antibiotics and many cancer treatments – make up around 90% of approved pharmaceutical drugs. Often, they bind at the active site of a target protein to prevent it from carrying out its known biological function.
But not all proteins can be targeted in this way: around 80% of disease-related proteins can’t be bound by traditional small molecule drugs.
This is often because they lack a well-defined binding site, or because the binding site is difficult to access.
Targeted protein degradation (TPD) takes a different approach. Rather than binding to inhibit the target protein, TPD helps connect the target with a ubiquitin tag.
This marks the target for destruction by triggering the ubiquitin proteasome system – each cell’s natural waste disposal system – to break the target protein down.
Because TPD can work isn’t constrained to active sites, it offers great promise for targets that have previously been “undruggable” – potentially leading to new, much-needed therapies for complex conditions like cancer, infectious diseases and neurodegeneration.
Who to contact
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Jonathan Large
Read bio: Jonathan Large
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