The Bcr-Abl inhibitor GNF-7 inhibits necroptosis and ameliorates acute kidney injury by targeting RIPK1 and RIPK3 kinases.

Abstract

Necroptosis is a form of programmed, caspase-independent cell death that is involved in various pathologic disorders such as ischemia/reperfusion injury, acute kidney injury and inflammatory bowel diseases. Identification of necroptosis inhibitors has great therapeutic potential for the treatment of necroptosis-associated diseases. In this study, we identified that the Bcr-Abl inhibitor GNF-7 was a potent inhibitor of necroptosis. GNF-7 inhibited necroptosis in both human and mouse cells, while not protecting cells from apoptosis. Drug affinity responsive target stability assay (DARTS) demonstrated that it binded with RIPK1 and RIPK3. GNF-7 inhibited RIPK1 and RIPK3 kinase activities and thus disrupted RIPK1-RIPK3 necrosome complex formation. In vivo, GNF-7 ameliorated both cisplatin- and ischemia/reperfusion-induced AKI. Orally administration of GNF-7 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of AKI. Taken together, our study shows that GNF-7 is a novel necroptosis inhibitor and has great potential for the treatment of acute renal inflammatory disorders by targeting both RIPK1 and RIPK3 kinases.

• Authors: Xia Qin, Longmiao Hu, Shen-Nan Shi, Xiaofei Chen, Chunlin Zhuang, Wen Zhang, Siriporn Jitkaew, Xiufeng Pang, Jianqiang Yu, Ye-Xiong Tan, Hong-Yang Wang, Zhenyu Cai
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 177 Pg. 113947 (07 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32247850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido(4,5-d)pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
• Protein Kinase Inhibitors
• Pyrimidinones
• Fusion Proteins, bcr-abl
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Ripk3 protein, mouse
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, metabolism, prevention & control)
• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacology)
• Cell Line, Tumor
• Cells, Cultured
• Cisplatin (pharmacology, toxicity)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, metabolism)
• HT29 Cells
• Humans
• Male
• Mice, Inbred C57BL
• Molecular Structure
• Necroptosis (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidinones (chemistry, pharmacology)
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• U937 Cells