8RI2

Crystal structure of NLRP3 in complex with inhibitor NP3-562

This is a non-PDB format compatible entry.

Summary for 8RI2

• Entry DOI: 10.2210/pdb8ri2/pdb
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, 2-[4-chloranyl-9-oxidanylidene-12-(2-oxidanylpropan-2-yl)-5-thia-1,10,11-triazatricyclo[6.4.0.0^{2,6}]dodeca-2(6),3,7,11-tetraen-10-yl]-~{N}-[(3~{R})-1-methylpiperidin-3-yl]ethanamide, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: inflammasome, inhibitor, nlrp3, nalp3, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 65021.45

Authors

Dekker, C. (deposition date: 2023-12-18, release date: 2024-01-17, Last modification date: 2024-02-07)

Primary citation

Velcicky, J.,Janser, P.,Gommermann, N.,Brenneisen, S.,Ilic, S.,Vangrevelinghe, E.,Stiefl, N.,Boettcher, A.,Arnold, C.,Malinverni, C.,Dawson, J.,Murgasova, R.,Desrayaud, S.,Beltz, K.,Hinniger, A.,Dekker, C.,Farady, C.J.,Mackay, A.
Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.
J.Med.Chem., 67:1544-1562, 2024

PubMed 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 () could be optimized into an advanced compound 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 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, shows also a good overall development profile.

PubMed: 38175811
DOI: 10.1021/acs.jmedchem.3c02098

Experimental method

X-RAY DIFFRACTION (2.8 Å)