Development of DUB inhibitors for diseases of high unmet need
Research type
Research Study
Full title
Development of first in class selective inhibitors targeting deubiquitylating enzymes for treatment of diseases with high unmet need
IRAS ID
231935
Contact name
Paul Thompson
Contact email
Sponsor organisation
Mission Therapeutics
Duration of Study in the UK
4 years, 11 months, 31 days
Research summary
Research Summary
Mission has established a rich pipeline of first in class DUB inhibitor programmes that are rapidly progressing towards clinical development, and alongside, the identification of a patient selection strategy is one of huge importance for these programmes.
Clinical development and patient selection is at the heart of all Mission’s projects, and the ability to predict which drug will work for which patient, is not only desirable but essential if unnecessary risk is to be avoided to individuals who would not benefit from taking the drug. The need for biomarkers that allow us to predict patient responders based on their genomic or proteomic makeup, will allow us to target drug treatments we know will work.
Mission Therapeutics research project therefore aims to address the following:
1. Develop first in class DUB inhibitors aimed at specific biomolecular targets in the diseased tissue.
2. Discover a pharmacodynamic biomarker that can measure the effectiveness of the drug on the target.
3. Discover biomarker(s) based on the genomic or proteomic profile of the patient that will enable prediction of whether the drug will provide therapeutic benefit in the disease.All three goals will allow better and more efficient treatments for the appropriate disease indication with fewer unnecessary failures or side effects.
Summary of Results
The objectives of this project were to develop first in class selective inhibitors targeting deubiquitylating enzymes for the treatment of diseases with high unmet need. To enable this research, the team needed to:
- Demonstrate our target of interest is expressed in the context of disease,
- Develop a pharmacodynamic biomarker to allow them to measure engagement and efficacy of the drug on the target (ie measure how well the drug is working in the patient).
- Develop a biomarker that can predict which patient population will benefit from taking the drug ( ie in which patients the drug will work)
Normal and diseased samples were ethically procured from appropriate human tissue sources (established human tissue or blood banks) and usage remained within sample type and number limits as permitted by the study protocol
Through the use of these human samples, Mission was able to achieve key study objectives
- A key drug target, USP30, was demonstrated to be expressed in tissues of interest for treatment development, including kidney, lung and brain
- For development of a pharmacodynamic biomarker, USP30 was detected in blood, skin, urine cells and buccal swabs
- Blood was chosen as the sample type best suited for biomarker development. A pharmacodynamic assay for USP30 inhibitors has been developed using blood samples, an assay which can be transferred for use in clinical trials
All samples and records have been appropriately handled in accordance with study protocol requirements.
REC name
West of Scotland REC 5
REC reference
17/WS/0175
Date of REC Opinion
9 Aug 2017
REC opinion
Favourable Opinion