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Case study

Developing novel small molecules as inhibitors of the NLRP3 inflammasome

Lead PI: Prof David Brough, University of Manchester, UK

Start of grant
Project completes and Consortium publishes results
Prof Brough collaborates with Oxford Drug Discovery Institute to continue in pursuit for small molecule inhibitors
NLRP3 timeline

2015

Dementia Consortium funds project

2018

Project completes and Consortium publishes results

2019

Prof Brough collaborates with Oxford Drug Discovery Institute to continue in pursuit for small molecule inhibitors

In addition to Alzheimer’s disease, the NLRP3 inflammasome contributes to various neurodegenerative disorders including Parkinson’s disease, inflammatory ageing and age-related cognitive decline. Emerging data highlight the potential of the NLRP3 inflammasome as an exciting therapeutic target for the treatment of dementia. By inhibiting the NLRP3 inflammasome, the production of neurotoxic IL-1β is prevented, which promotes microglial survival facilitating Aβ phagocytosis and its removal. Animal studies suggest that NLRP3-dependent inflammation is causative to the memory deficits associated with AD and it is known that once formed NLRP3 inflammasome specks are released, they become systemic, and propagate further NLRP3-dependent inflammation.

Prof David Brough

University of Manchester, UK

“The grant employed a postdoc in Manchester for a short period. We were able to achieve a publication which helps career development.”

“The project was stopped not due to lack of scientific interest but there were no avenues left open to explore at the time of closure. Other avenues we could have pursued for this project were already being carried out by the PI”

Outcomes

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Developed and characterised a small molecule tool kit/assay to interrogate NLRP3 inflammasome dependent responses.  NLRP3/IL1 is now emerging as a inflammatory drug target for dementia and other indications

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Identified and characterised potent and well characterised small molecule reagents that can act at different points in the NLRP3 pathway

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Collaboration with the Drug Discovery Alliance has produced 3 publications on NLRP3 in the past 2 years. Prof Brough has published 30 papers on NLRP3 in the past 5 years

Publication

Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses. Redondo-Castro E, Faust D, Fox S, Baldwin AG, Osborne S, Haley MJ, Karran E, Nuthall H, Atkinson PJ, Dawson LA, Routledge C, Allan SM, Freeman S, Brownlees J, Brough D. Sci Rep. 2018 Apr 4;8(1):5667. doi: 10.1038/s41598-018-24029-3.