9HG4

NACHT domain of NLRP3 in complex with DFV890

This is a non-PDB format compatible entry.

Summary for 9HG4

• Entry DOI: 10.2210/pdb9hg4/pdb
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, 1-[azanyl-oxidanylidene-[2-(2-oxidanylpropan-2-yl)-1,3-thiazol-5-yl]-$l^{6}-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: inflammasome, nalp3, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 65004.06

Authors

Dekker, C. (deposition date: 2024-11-18, release date: 2025-03-19, Last modification date: 2025-03-26)

Primary citation

Shen, D.M.,Byth, K.F.,Bertheloot, D.,Braams, S.,Bradley, S.,Dean, D.,Dekker, C.,El-Kattan, A.F.,Franchi, L.,Glick, G.D.,Ghosh, S.,Hinniger, A.,Katz, J.D.,Kitanovic, A.,Lu, X.,Olhava, E.J.,Opipari, A.W.,Sanchez, B.,Seidel, H.M.,Stunden, J.,Stutz, A.,Telling, A.,Venkatraman, S.,Winkler, D.G.,Roush, W.R.
Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor.
J.Med.Chem., 68:5529-5550, 2025

PubMed Abstract: The discovery of DFV890 (()-), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 (()-), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 (()-) was also effective in an air pouch model of gout.

PubMed: 40036600
DOI: 10.1021/acs.jmedchem.4c02759

Experimental method

X-RAY DIFFRACTION (2.771 Å)