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.
- 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: [email protected].
- 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: [email protected].
- 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: [email protected].
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.