7FCZ

Crystal Structure of human RIPK1 kinase domain in complex with a novel inhibitor

7FCZ の概要

• エントリーDOI: 10.2210/pdb7fcz/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, N-[(3S)-7-(2-cyclopropylethynyl)-5-methyl-4-oxidanylidene-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(phenylmethyl)-4H-1,2,4-triazole-3-carboxamide (3 entities in total)
• 機能のキーワード: immune system-inhibitor complex, immune system/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68250.82

構造登録者

Su, H.X.,Xie, H.,Nie, T.Q.,Li, M.J.,Xu, Y.C. (登録日: 2021-07-15, 公開日: 2022-01-19, 最終更新日: 2023-11-29)

主引用文献

Yang, X.,Lu, H.,Xie, H.,Zhang, B.,Nie, T.,Fan, C.,Yang, T.,Xu, Y.,Su, H.,Tang, W.,Zhou, B.
Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis.
Angew.Chem.Int.Ed.Engl., 61:e202114922-e202114922, 2022

PubMed Abstract: Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.

PubMed: 34851543
DOI: 10.1002/anie.202114922

実験手法

X-RAY DIFFRACTION (2.21 Å)