Using chemical-genetics to inhibit and characterise “undruggable” enzymes

The ability to inhibit kinases with small molecule drugs has transformed our understanding of signalling networks. It has allowed us to define the substrates and processes that each kinase controls, and to map how these enzymes cooperate within signalling pathways. This has also revolutionised the treatment of diseases such as cancer, with currently 76 kinase inhibitors approved for clinical use. This could be the tip of the iceberg, since our cells use many other types of enzymes, and yet the vast majority of these are not currently inhibitable with small molecule drugs. Therefore, new strategies to inhibit these enzymes could transform many fields of research and provide new opportunities for disease treatment.

We have developed a chemical-genetic system that will allow different enzymes to be inhibitable with a small molecule drug. The principle is that a drug can be used to recruit small inhibitory peptides that inhibit enzyme function by blocking key protein: protein interaction interfaces needed for activity and/or substrate co-localisation. We demonstrate that this system allows the rapid inhibition of PP2A-B56 - a major serine/threonine phosphatase complex that is currently undruggable - by recruiting a short peptide that blocks the substrate binding groove on the enzyme complex. By using this strategy to rapidly inhibit PP2A-B56 (within seconds) we have been able to characterise its direct substrates and phenotypes, in a manner that was not previously possible.

This studentship will build on this strategy to develop a method to inhibit three other phosphatase complexes with known substrate-binding motifs, and then potentially expand the system into other enzymes classes, all of which are currently undruggable. The modularity of this system will ensure that such a widespread approach is feasible. The student will use this system to characterise how these different enzymes work, performing mass-spectrometry to identify their direct substrates. They will also use a range of cell biology techniques, including live and fixed cell microscopy, to characterise the processes that these enzymes control. This will provide broad training for the student, and it will allow them to develop a technology that could transform many different fields of research, potentially revealing new avenues for disease treatment.

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