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

doi:10.1016/j.bcp.2020.113947

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

Biochem Pharmacol. 2020 Jul:177:113947. doi: 10.1016/j.bcp.2020.113947. Epub 2020 Apr 2.

Authors

Xia Qin¹, Longmiao Hu¹, Shen-Nan Shi², Xiaofei Chen³, Chunlin Zhuang³, Wen Zhang⁴, Siriporn Jitkaew⁵, Xiufeng Pang⁶, Jianqiang Yu⁷, Ye-Xiong Tan⁸, Hong-Yang Wang⁹, Zhenyu Cai¹⁰

Affiliations

¹ National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, PR China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China.
² Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
³ School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
⁴ School of Medicine, Tongji University, Shanghai 200092, PR China.
⁵ Faculty of Allied Health Sciences, Department of Clinical Chemistry, Chulalongkorn University, Bangkok 10330, Thailand.
⁶ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, PR China.
⁷ College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China.
⁸ National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, PR China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China. Electronic address: yxtan1214@163.com.
⁹ National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, PR China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China. Electronic address: hywangk@vip.sina.com.
¹⁰ National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, PR China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China. Electronic address: drcaizhenyu@126.com.

PMID: 32247850
DOI: 10.1016/j.bcp.2020.113947

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.

Keywords: Acute kidney injury; GNF-7; Necroptosis; RIPK1; RIPK3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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