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The Bcr-Abl Inhibitor GNF-7 Inhibits Necroptosis and Ameliorates Acute Kidney Injury by Targeting RIPK1 and RIPK3 Kinases

The Bcr-Abl Inhibitor GNF-7 Inhibits Necroptosis and Ameliorates Acute Kidney Injury by Targeting RIPK1 and RIPK3 Kinases

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

Biochem Pharmacol. 2020 Jul;177:113947.

PMID: 32247850

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP839706079	GNF-7		839706-07-9	Price

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