Molecular Glues offer alternative approach for Targeting Proteins

Researchers from the Francis Crick Institute, Imperial College London and Astrazeneca are working to advance discovery of ‘molecular glues’ that facilitate interaction between a protein previously considered to be ‘undruggable’ and a cellular enzyme, that is capable of modifying and degrading the disease-causing target protein. Once inactivated, or labelled for degradation by additional proteins recruited by the enzyme, the disease protein can then be disposed of by the body.

The research has received £11.2million in combined investments, including a Prosperity Partnership grant from the Engineering and Physical Sciences Research Council (EPSRC) and matching funds from AstraZeneca.

Ed Tate, Chair in Chemical Biology at Imperial College London and Group Leader at the Crick, said: “Most drug treatments currently used to treat disease are what we call small molecule drugs and in order to work, these small molecules have to specifically target and interact with disease-causing target proteins. 

“Challenges arise when we can’t find a small molecule with the ability to interact with certain proteins, those we call ‘undruggable’. But if we can redirect these harmful proteins towards the cell’s own waste disposal system, we could more effectively treat different diseases like cancer.”

The project will bring together 12 postdoctoral researchers from different scientific specialities and three PhD students, working across eight laboratories and scientific technology platforms at the Crick, all in close collaboration with scientists at Imperial College and AstraZeneca.

Veronique Birault, Director of Translation at the Crick, said: “This partnership exemplifies how we can harness close industry collaboration to accelerate translation of our research.”

Julian Downward, Associate Research Director and head of the Oncogene Biology Laboratory at the Crick, said: “By systematically screening for molecular glue degraders, we’re opening up many new opportunities to tackle some of the biggest health challenges. 

“In certain cancers like lung and pancreatic, there are tumour promoting, disordered proteins that we have struggled specifically to target with traditional drug discovery methods. These proteins will be an early focus of the project as we combine the expertise of chemical and cancer biologists. But there are also a number of other health conditions caused by the accumulation of harmful proteins, like neurodegenerative diseases where protein plaques in the brain slowly lead to cell death.”

Steve Fawell, Vice President, Head of Oncology Discovery at AstraZeneca, said: “Through this work, we have the opportunity to reach important oncology targets that were previously considered undruggable using traditional approaches. We are delighted to collaborate on this innovative research, which has the potential to bring new medicines to patients who need them the most.”

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