Periodic Reporting for period 1 - PyroScreen (Targeting NLRP3-mediated inflammation with novel chemotypes)
Okres sprawozdawczy: 2022-10-01 do 2024-03-31
Inflammasomes serve a crucial role in safeguarding humans against pathogenic microorganisms, harmful substances, and cellular changes that may lead to illness. Among these, the NLRP3 inflammasome garners significant attention due to its pivotal role in various chronic inflammatory diseases stemming from abnormal NLRP3 activation. Additionally, mutations resulting in NLRP3 gain-of-function give rise to cryopyrin-associated periodic syndrome (CAPS), a periodic fever syndrome. Despite considerable interest, most clinical-grade NLRP3 inhibitors are derived from the sulfonylurea inhibitor CRID3, also known as MCC950. Recently, several companies have advanced CRID3-derived NLRP3 inhibitors into human studies. However, a notable concern with CRID3 is the potential for drug-induced liver injury with chronic exposure. Moreover, the inhibitory efficacy of CRID3 is reduced by disease-associated mutations within and surrounding the NLRP3 NACHT domain in preclinical mouse models of CAPS and in LPS-stimulated PBMCs of CAPS patients. Additionally, carbonic anhydrase II (CA II) has been identified as an off-target for this compound class. Hence, there is an urgent need to discover novel, potent, and selective NLRP3-targeted inhibitors with distinct chemical scaffolds to open up novel avenues for further clinical development of NLRP3-targeted therapeutics.
We have identified and characterized a novel class of non-sulfonylurea compounds that inhibit the NLRP3 inflammasome with 10-fold higher potency than MCC950/CRID3. We showed that they target NLRP3 directly, showed that they physically bind with high potency to the recently reported CRID3 binding pocket in the NACHT domain, and performed an in-depth functional analysis of the activity, selectivity and molecular mechanism of action of this novel inhibitor class in both preclinical disease models and human CAPS patient samples.
A manuscript detailing our findings has been published in a peer-reviewed scientific journal (PMID: 38519142). In conclusion, the work presented in project PyroScreen helped to expand the pipeline of NLRP3-targeted therapeutics with a new class of non-sulfonylurea-based NLRP3-inhibitors.