8RI2

Crystal structure of NLRP3 in complex with inhibitor NP3-562

これはPDB形式変換不可エントリーです。

8RI2 の概要

• エントリーDOI: 10.2210/pdb8ri2/pdb
• 分子名称: 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)
• 機能のキーワード: inflammasome, inhibitor, nlrp3, nalp3, immune system
• 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: 65021.45

構造登録者

Dekker, C. (登録日: 2023-12-18, 公開日: 2024-01-17, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)