Development of DUB inhibitors

• Research type

  Research Study

• Full title

  Development of DUB inhibitors

• IRAS ID

  315520

• Contact name

  Paul Thompson

• Contact email

  pthompson@missiontherapeutics.com

• Sponsor organisation

  Mission Therapeutics

• Duration of Study in the UK

  4 years, 11 months, 31 days

• Research summary

  Summary of Research

  Mission Therapeutics is a specialised drug discovery company focused on the development of small molecule inhibitors targeting DUBs to treat diseases of high unmet need including indications such as neurodegeneration, mitochondrial disorders, and fibrosis.

  Clinical development and patient selection is key for 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.

  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 pharmacodynamic biomarkers 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.

  Examples of human biospecimen usage supporting this success under Mission’s NHS REC approved project (17/WS/0175) over the last 4.5 years includes:

  • IHC antibody method validation and subsequent establishment of target / substrate expression understanding in human tissue sections by Immunohistochemistry staining
  • Use of whole human blood enabling measurement of drug target engagement for useclinical trials

  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 previously demonstrated to be expressed in tissues of interest for treatment development, including kidney, lung and brain - For development of a pharmacodynamic biomarker, Blood was chosen as the sample type best suited for USP30 biomarker development. A pharmacodynamic assay for USP30 inhibitors was developed using prospectively collected blood samples from pre-existing REC approved blood donation protocols. This assay potentially could be transferred for use in clinical trials, of USP30 inhibitors. All samples and records have been appropriately handled in accordance with study protocol requirements.
  

• REC name

  HSC REC B

• REC reference

  22/NI/0100

• Date of REC Opinion

  16 May 2022

• REC opinion

  Favourable Opinion