Targeting NLRP3-mediated inflammation with novel chemotypes

Introduction

Inflammasomes play a vital role in protecting humans against pathogenic microorganisms, harmful substances, and cell changes that could result in illness. The NLRP3 inflammasome, in particular, attracts considerable interest because aberrant NLRP3 activation is a key pathogenic mechanism in many chronic inflammatory diseases.

Background

Moreover, gain-of-function mutations in NLRP3 cause a periodic fever syndrome named cryopyrin-associated periodic syndrome (CAPS). MCC950/CRID3-based sulfonylurea compounds are currently the only reported class of inhibitors that selectively target NLRP3 with nM potency.

Current Research

We and others recently showed that members of this sulfonylurea class of inhibitors directly target the central NACHT domain of NLRP3. Several companies have recently progressed MCC950/CRID3-derived NLRP3 inhibitors to human studies. However, there is an urgent need to expand the pipeline of NLRP3-targeted therapeutics with NLRP3 inhibitors of novel chemotypes.

Objectives

Based on exciting preliminary data, we aim to:

1. Identify novel NLRP3 inflammasome inhibitors.
2. Perform an in-depth functional analysis of their activity, selectivity, and molecular mechanism of action.
3. Define the market potential and explore the best strategy towards clinical development with partner organizations.

Conclusion

In conclusion, the project will help to expand the pipeline of NLRP3-targeted therapeutics with new NLRP3 inhibitors. If successful, the project may meaningfully impact the lives of many patients that suffer from NLRP3-mediated diseases in Europe and across the globe.