7XMK

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

Summary for 7XMK

• Entry DOI: 10.2210/pdb7xmk/pdb
• Descriptor: 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)
• Functional Keywords: ripk1, kinase, complex, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 68184.34

Authors

Zhang, L.,Wang, Y.,Li, Y.,Yang, S. (deposition date: 2022-04-26, release date: 2023-04-26, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.376 Å)