7XMK

Crystal structure of human RIPK1 kinase domain in complex with compound SKLB923

7XMK の概要

• エントリーDOI: 10.2210/pdb7xmk/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, IODIDE ION, 5-[2-(cyclopropylcarbonylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-N-[(1S)-1-(3-fluorophenyl)ethyl]-1-methyl-indole-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: ripk1, kinase, complex, inhibitor, transferase
• 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: 68184.34

構造登録者

Zhang, L.,Wang, Y.,Li, Y.,Yang, S. (登録日: 2022-04-26, 公開日: 2023-04-26, 最終更新日: 2024-05-15)

主引用文献

Zhang, L.,Li, Y.,Tian, C.,Yang, R.,Wang, Y.,Xu, H.,Zhu, Q.,Chen, S.,Li, L.,Yang, S.
From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases.
J.Med.Chem., 67:754-773, 2024

PubMed Abstract: Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cellular necroptosis, which is considered as an important therapeutic target for necroptosis-related indications. Herein, we report the structural optimization and structure-activity relationship investigations of a series of eutectic 5-substituted-indole-3-carboxamide derivatives. The prioritized compound exhibited low nanomolar IC values against RIPK1 and showed good kinase selectivity. Based on its eutectic structure, occupied both the allosteric and ATP binding pockets of RIPK1, making it a potent dual-mode inhibitor of RIPK1. , had a potent protective effect against necroptosis in cells. Compound also provided robust protection in a TNFα-induced systemic inflammatory response syndrome (SIRS) model and imiquimod (IMQ)-induced psoriasis model. It also showed good pharmacokinetic properties and low toxicity. Overall, is a promising lead compound for drug discovery targeting RIPK1 and warrants further study.

PubMed: 38159286
DOI: 10.1021/acs.jmedchem.3c02102

実験手法

X-RAY DIFFRACTION (2.376 Å)