Molecular glues to tackle ‘undruggable’ disease targets
Researchers at the Francis Crick Institute, Imperial College London and AstraZeneca will advance the discovery of new ‘molecular glues’ to treat a range of different diseases, thanks to a £11.2million combined investment, including a Prosperity Partnership grant from the Engineering and Physical Sciences Research Council (EPSRC) and matching funds from AstraZeneca announced today.
The teams will develop a rule book for the discovery of new molecular glue degraders, with a focus on targeting proteins considered to be ‘undruggable’ by conventional treatment options.
Molecular glues bring together proteins that wouldn’t normally interact, so until recently, they have generally been discovered by accident. In the treatment of disease, they can orchestrate modification and degradation of disease-causing target proteins, by redirecting them to the cell’s natural waste disposal system.
They work by facilitating interaction between a target protein and a cellular enzyme. The target protein is inactivated or labelled for degradation by additional proteins recruited by the enzyme.
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-casing 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 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 it, 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.”
Dr Andrew Bourne, Director of Partnerships at EPSRC said: “Prosperity Partnerships demonstrate how business and academia can come together to co-create and co-deliver research and innovation that address industry-driven challenges and deliver economic and societal impact. These new projects showcase the breadth of research and innovation in the UK, covering a wider range of sectors, and support the UK’s ambitions to be a science superpower and an innovation nation.”