Revolving around the ubiquitin‒proteasome system: USP2-targeted degrader

Project Information

USP2-TD

Grant agreement ID: 101025271

DOI

10.3030/101025271

Project closed

EC signature date 8 April 2021

Start date 1 October 2021

End date 30 September 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 1 - USP2-TD (Revolving around the ubiquitin‒proteasome system: USP2-targeted degrader)

Reporting period: 2021-10-01 to 2023-09-30

Summary of the context and overall objectives of the project

This project deals with the discovery of an appropriate chemical tool that allows the study of a protein. This protein is called ubiquitin-specific protease 2 (USP2) and belongs the superfamily of deubiquitinating enzymes (DUBs). While USP2 has been associated with a wide variety of cancers and represents a very promising therapeutic target, it still requires to be validated for its therapeutic potential. In that context, having an appropriate chemical tool would allow a confident interrogation and further understanding of USP2 biology and disease. This tool can likewise serve as starting point and eventually feed drug discovery projects for USP2-targeted treatments. To this end, an innovative approach endowed with great potential has recently emerge. This technology is called proteolysis-targeting chimera (PROTAC) and consists of pursuing the degradation of a protein that is upregulated, thereby evoking a certain disease. Herein, we aimed at the development of an USP2-targeted degrader (USP2-TD) based on PROTAC technology. This research has been carried out in the Spring group at the University of Cambridge and involved a 6-month placement in the Ciulli group at the University of Dundee.

At the time of the end of the action, the project is still ongoing. Preliminary data showed two major findings:
- We identified a candidate with the potential to become an USP2-TD.
- We discovered a natural interaction between USP2 and an unrelated complex of proteins.
Given these promising results, these projects will be investigated in a collaboration between the Universities of Barcelona, Cambridge, and Dundee. Success in these studies can lead to major advances in the knowledge and treatment of USP2-related diseases.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We performed computational studies to analyse USP2 surface and test its availability to be degraded using PROTAC technology. Upon confirmation, we embarked in the rational design of several series of dual molecules (USP2-TD candidates), which were later tested for their capacity to trigger USP2 degradation in some cell lines. These experiments showed the success of one of the USP2 candidates to effectively degrade the protein. However, an optimisation process on this candidate molecule is still required in order to achieve a complete and profound degradation of USP2, i.e. the chemical tool we are looking for.
Once the work is complete, this USP2-TD chemical tool will be available for biologist to study USP2 biology and disease. The research will be published in scientific journals and presented at conferences. Concurrently, it will be presented in different events directed to the general public.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project has the potential to open a new pathway for the treatment of diseases with dysregulated levels of USP2 protein, which are diseases yet to be fully understood. Thereby, an USP2-TD will allow the elucidation of this protein functions and implications in disease.

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