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Updated: Jul 6, 2025
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors
Juraj Velcicky1, Philipp Janser1, Nina Gommermann1
1Novartis Biomedical Research, CH-4002 Basel, Switzerland.
Abstract:
NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1β and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1β release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile.
Insights
Researchers discovered a novel compound, NP3-562, that effectively inhibits the NLRP3 inflammasome, a key factor in numerous inflammatory diseases. This finding offers a promising new therapeutic avenue for conditions linked to NLRP3 activation.
Area of Science:
- Molecular biology
- Immunology
- Drug discovery
Background:
- The NLRP3 inflammasome acts as a cellular sensor for danger signals, initiating inflammatory responses.
- NLRP3 inflammasome activation is implicated in various diseases, including metabolic disorders, neurodegenerative conditions, and cancer.
- Targeting NLRP3 offers a potential therapeutic strategy for a wide range of inflammatory conditions.
Purpose of the Study:
- To identify novel small molecules that inhibit NLRP3 inflammasome assembly and activation.
- To characterize the binding mode and in vivo efficacy of a newly discovered NLRP3 inhibitor.
Main Methods:
- High-throughput screening was employed to identify a novel NLRP3-binding scaffold.
- Hit compound optimization led to the development of NP3-562.
- In vitro assays using human whole blood and in vivo studies in a mouse model of acute peritonitis were conducted to assess compound potency and efficacy. X-ray crystallography was used to determine the binding mode.
Main Results:
- A novel tricyclic scaffold was identified through high-throughput screening.
- The optimized compound, NP3-562, demonstrated potent inhibition of IL-1β release in human whole blood.
- NP3-562 achieved full inhibition of IL-1β release in a mouse acute peritonitis model at 30 mg/kg. X-ray structure revealed a unique binding mode distinct from known inhibitors.
Conclusions:
- NP3-562 represents a novel, potent inhibitor of the NLRP3 inflammasome with a unique binding mechanism.
- The compound exhibits promising efficacy in preclinical models and possesses a favorable development profile.
- This discovery provides a new chemical entity for the development of therapeutics targeting NLRP3-mediated diseases.
