9GU4

Crystal structure of NLRP3 in complex with inhibitor NP3-253

これはPDB形式変換不可エントリーです。

9GU4 の概要

• エントリーDOI: 10.2210/pdb9gu4/pdb
• 関連するPDBエントリー: 8RI2
• 分子名称: NACHT, LRR and PYD domains-containing protein 3, 2-[6-[[(3R)-1-ethylpiperidin-3-yl]amino]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: inhibitor, atpase, inflamasome, 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: 64963.91

構造登録者

Srinivas, H. (登録日: 2024-09-18, 公開日: 2024-12-11, 最終更新日: 2024-12-25)

主引用文献

Mackay, A.,Velcicky, J.,Gommermann, N.,Mattes, H.,Janser, P.,Wright, M.,Dubois, C.,Brenneisen, S.,Ilic, S.,Vangrevelinghe, E.,Stiefl, N.,Boettcher, A.,Schoenboerner, M.,Vogelsanger, M.,Muller-Bentz, S.,Kamke, M.,Rubert, J.,Kauffmann, M.,Desrayaud, S.,Trunzer, M.,Srinivas, H.,Hinniger, A.,von Burg, N.,Beltz, K.,Dekker, C.,Farady, C.J.
Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome.
J.Med.Chem., 67:20780-20798, 2024

PubMed Abstract: Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer's disease and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign. The scaffold, exemplified by lead molecule , has excellent potency and physicochemical and pharmacokinetic properties, including good brain penetration. The establishment of pharmacokinetic/pharmacodynamic relationships in the periphery and central nervous system in mechanistic models facilitates the use of as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models.

PubMed: 39574318
DOI: 10.1021/acs.jmedchem.4c02350

実験手法

X-RAY DIFFRACTION (2.696 Å)