9MGY

Cryo-EM structure of Human NLRP3 complex with compound 1

This is a non-PDB format compatible entry.

Summary for 9MGY

• Entry DOI: 10.2210/pdb9mgy/pdb
• EMDB information: 48263
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, ADENOSINE-5'-TRIPHOSPHATE, (2M)-2-(6-{[(3R)-1-methylpiperidin-3-yl]amino}pyridazin-3-yl)-5-(trifluoromethyl)phenol, ... (4 entities in total)
• Functional Keywords: nlrp3, cryo-em, small molecule inhibitor, inflammasome, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 119183.07

Authors

Mammoliti, O.,Carbajo, R.J.,Perez-Benito, L.,Yu, X.,Prieri, M.L.C.,Bontempi, L.,Embrechts, S.,Paesmans, I.,Bassi, M.,Bhattacharya, A.,Roman, S.C.,Hoog, S.D.,Demin, S.,Gijsen, H.J.M.,Hache, G.,Jacobs, T.,Jerhaoui, S.,Leenaerts, J.,Lutter, F.H.,Matico, R.,Oehlrich, D.,Perrier, M.,Ryabchuk, P.,Schepens, W.,Sharma, S.,Somers, M.,Suarez, J.,Surkyn, M.,Opdenbosch, N.V.,Verhulst, T.,Bottelbergs, A. (deposition date: 2024-12-11, release date: 2025-02-26)

Primary citation

Mammoliti, O.,Carbajo, R.,Perez-Benito, L.,Yu, X.,Prieri, M.L.C.,Bontempi, L.,Embrechts, S.,Paesmans, I.,Bassi, M.,Bhattacharya, A.,Canellas, S.,De Hoog, S.,Demin, S.,Gijsen, H.J.M.,Hache, G.,Jacobs, T.,Jerhaoui, S.,Leenaerts, J.,Lutter, F.H.,Mahieu, M.,Matico, R.,Miller, R.,Oehlrich, D.,Perrier, M.,Ryabchuk, P.,Schepens, W.,Sharma, S.,Somers, M.,Suarez, J.,Surkyn, M.,Van Opdenbosch, N.,Verhulst, T.,Bottelbergs, A.
Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity.
J.Med.Chem., 2025

PubMed Abstract: NLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1β, and pyroptosis, a regulated cell death. Mounting evidence associates excessive NLRP3 activation to neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases. Thus, NLRP3 inhibitors could potentially provide therapeutic benefit for these disorders. We describe here the evolution of inhibitors relying on a pyridazine-based motif for their key interactions with NLRP3. A Cryo-EM structure helped optimizing protein-ligand complementarity. Subsequently, conformational NMR studies pointed the efforts toward 5,6-bicyclic cores that allowed a balance between brain penetration and undesirable properties, such as hERG inhibition. The effort culminated in compound , which showed moderate (mouse) to good (rat) brain penetration and was active at low dose in an LPS challenge model. Importantly, an earlier compound was active in a central neuroinflammation model providing a valuable proof of concept for NLRP3 inhibition.

PubMed: 39932543
DOI: 10.1021/acs.jmedchem.4c03108

Experimental method

ELECTRON MICROSCOPY (2.9 Å)