8ETR

CryoEM Structure of NLRP3 NACHT domain in complex with G2394

Summary for 8ETR

• Entry DOI: 10.2210/pdb8etr/pdb
• EMDB information: 28596
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: nlrp3, nacht, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 64263.35

Authors

Murray, J.M.,Johnson, M.C. (deposition date: 2022-10-17, release date: 2022-11-02, Last modification date: 2024-06-19)

Primary citation

McBride, C.,Trzoss, L.,Povero, D.,Lazic, M.,Ambrus-Aikelin, G.,Santini, A.,Pranadinata, R.,Bain, G.,Stansfield, R.,Stafford, J.A.,Veal, J.,Takahashi, R.,Ly, J.,Chen, S.,Liu, L.,Nespi, M.,Blake, R.,Katewa, A.,Kleinheinz, T.,Sujatha-Bhaskar, S.,Ramamoorthi, N.,Sims, J.,McKenzie, B.,Chen, M.,Ultsch, M.,Johnson, M.,Murray, J.,Ciferri, C.,Staben, S.T.,Townsend, M.J.,Stivala, C.E.
Overcoming Preclinical Safety Obstacles to Discover ( S )- N -((1,2,3,5,6,7-Hexahydro- s -indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5 H -pyrazolo[5,1- b ][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor.
J.Med.Chem., 65:14721-14739, 2022

PubMed Abstract: Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel NLRP3 inhibitors that could minimize the risk of drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric to identify a series of 6,7-dihydro-5H-pyrazolo[5,1-][1,3]oxazinesulfonylureas. A leading compound from this series was advanced into safety studies in cynomolgus monkeys, and renal toxicity, due to compound precipitation, was observed. To overcome this obstacle, we focused on improving the solubility of our compounds, specifically by introducing basic amine substituents into the scaffold. This led to the identification of GDC-2394, a potent and selective NLRP3 inhibitor, with an in vitro and in vivo safety profile suitable for advancement into human clinical trials.

PubMed: 36279149
DOI: 10.1021/acs.jmedchem.2c01250

Experimental method

ELECTRON MICROSCOPY (3.5 Å)