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Development of NLRP3-ASC selective inhibitors

Research Project
 | 
01.05.2020
 - 01.11.2021

During an attack from pathogens organisms produce inflammatory cytokines, such as IL-1β and IL-18, that act to combat infection. However, prolonged and uncontrolled production of inflammatory cytokines, usually due to sterile inflammatory triggers, causes chronic inflammation. The latter is the underlying cause of several (auto)-inflammatory diseases such as gout, CAPS (Cryopyrin-Associated Periodic Syndromes), arthritis, Alzheimer's disease, etc. The main cellular node activated by sterile (auto)-inflammatory triggers is NLRP3-inflammasome (NACHT, LRR and PYD domains-containing protein 3). Main drugs against chronic inflammation act downstream of the NLRP3-inflammasome by targeting the release of inflammatory cytokines, with variable efficacity. However, these drugs block the entire inflammatory response, as such, an increase in the rate of infections is a main concern. Alternatively, blocking specifically the NLRP3-inflammasome would inhibit only one branch of the innate immune response having an immense potential to treat (auto)-inflammatory disorders with fewer side effects. As of today, there are no NLRP3-inflamasome targeting drugs on the market. To develop such an inhibitor, we are focusing on 11 small molecules obtained from a cell-based screen of over 10'000 compounds. Our small molecules have novel chemistry to the known NLRP3 inhibitors and, without optimization, show NLRP3-inflammasome inhibitor activity comparable to known NLRP3 inhibitors. During the course of this feasibility study, we will perform hit-to-lead optimization and find the molecular mechanism of action of our compounds. We aim for a business-to-business model. By combining the expertise of our team in structural biology, immunology, organic chemistry and animal experimentation we will generate intellectual property that we can patent, and use as leverage to find business partners to push our compounds towards Phase I clinical trials.

Funding

Development of NLRP3-ASC selective inhibitors

Innosuisse Projekt (GrantsTool), 05.2020-11.2021 (19)
PI : Hiller, Sebastian.

Members (1)

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Sebastian Hiller

Principal Investigator