Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome

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 research described in this proposal 'Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome' has the potential to impact not only academic and industrial researchers working in a wide range of disciplines, but also the UK economy by the generation of intellectual property, and society by the generation of novel therapeutic strategies.
Cell signalling virtually entirely relies on post-translational modifications of proteins, including the addition/removal of ubiquitin, in the ubiquitin system (US). The role of deubiquitylases (DUBs) recently emerged as being central to the regulation of cell homeostasis and as such, many DUBs are closely linked to proliferative pathologies. As druggable enzymes, the present proposal aims at providing target validation and new therapeutic intervention avenues for the treatment of cancers. Economic and societal impacts will be facilitated through direct engagement with industrial stakeholders and through engagement with academic beneficiaries, providing them with new tools and capacity for additional economic and societal impact in the longer term. The potential impact of our work is detailed below;

This research will bring advances in; (i) synthetic chemistry relevant to the field of metallo-dependent DUBs and of asymmetric amino acid synthesis and peptide medicinal chemistry; (ii) chemical biology tools to further basic and applied research in the area of the US. The results of this work will be disseminated to the academic community by way of publication in high-impact journals and presented at national/international conferences and research institutions.
Where appropriate, the research results will be communicated in the form of a press release, via internet media communication, as well as through scientific networks. We will aim to expand existing scientific networks and to create new ones during the course of this project. This work will also give training opportunities for the researchers employed on the project. Scientific exchanges will represent opportunities for further training and networking of the personnel linked to this project through placements in other laboratories, as well as for training researchers from other groups across our respective networks. We will establish several scientific exchanges within our networks during the course of the project.

The peptidomimetics developed in this project could lead to strong economic impact through exploitation by academic and commercial partners; (i) as tools for target validation of the COP9 signalosome (CSN) in specific cancers; (ii) as starting points for the rational design of lead molecules targeting the CSN; (iii) as initial reagents to comprehensively investigate the Zn-dependent DUB sub-family that contains other members with links to diseases; (iv) as licensed tools for the community. We will make validated molecular tools available to the academic and industrial communities to enable further research. Further partnership and/or an exploitation license with the private sector will be sought out for promising molecules.

The work that we propose is directly linked to chemical and biomedical innovation and therefore has strong potential impact on the economy and on society, on a long time scale. One of the important potential impacts of this work is related to health in the domain of oncology. Our work would contribute to the development of a new therapeutic intervention strategy in these cancers via comprehensive target validation, the rational development of drug leads and tools to assess small molecule target engagement. These aspects could alleviate the suffering of people with these cancers and lead to the modification of policies. We aim to contribute to novel targeted therapeutic intervention routes in oncology and as such to provide an improved quality of life for patients affected by cancer through the development of specific compounds.