8ETR

CryoEM Structure of NLRP3 NACHT domain in complex with G2394

8ETR の概要

• エントリーDOI: 10.2210/pdb8etr/pdb
• EMDBエントリー: 28596
• 分子名称: NACHT, LRR and PYD domains-containing protein 3, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: nlrp3, nacht, inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 64263.35

構造登録者

Murray, J.M.,Johnson, M.C. (登録日: 2022-10-17, 公開日: 2022-11-02, 最終更新日: 2024-06-19)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.5 Å)