The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme. DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function. We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.

The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme. DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function. We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.

Small molecule drugs continue to dominate our collective ability to treat disease. However, the pharmaceutical industry faces challenges on several fronts, and increasing productivity has been framed as the grand challenge for the sector. Against a background of increasingly cost-constrained healthcare systems, the cost of launching new drugs is increasingly high (recently estimated at £1.8 Bn for each new drug!). In order to improve productivity in drug discovery, it is necessary to develop innovative new medicines that address currently unmet medical needs. Protein-protein interactions represent a significant untapped, but challenging, opportunity for treating diseases including cancer, inflammatory disease, cardiovascular disease and infection. Drugs function by binding to a protein target within the body. Most existing small molecule drugs bind to well-defined pockets in proteins - analogous to a key fitting into a lock. In stark contrast, the design of drugs to inhibit protein-protein interactions generally requires a fundamentally different type of interaction of the drug with its protein target - analogous to a hand gripping a ball. Thus, the development of effective drugs that target protein-protein interactions raises new challenges that need to be met in future drug discovery. This programme will develop new tools and understanding that will facilitate future drug discovery against protein-protein interactions. We will develop computational tools to classify protein-protein interactions according to their underlying 3D structure and the probability that they can be inhibited using small molecules. We will then exploit these computational tools to design classes of small molecule that can be prepared readily using state-of-the-art synthetic methods, and that are predisposed to target different types of protein-protein interaction. The resulting small molecule inhibitors will be made available to biological researchers to help understand the role of protein-protein interactions in disease. In addition, the new tools will be made accessible to the research community to facilitate the early-stage discovery of small molecule drugs that target protein-protein interactions. The programme will benefit from the input of major pharmaceutical companies, smaller drug discovery companies, a not-for-profit drug discovery organisation, and international academics. The involvement of a wide range of experts is essential because of the increasing trend for early stage drug discovery to be conducted by a range of organisations (both industry and academic), especially for more challenging target classes. Thus, together with wider research community engagement, we will ensure that the required future capabilities for early-stage drug discovery against protein-protein interactions are met.