2. Academic Validation
  3. 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

  • Biochem Pharmacol. 2020 Jul;177:113947. doi: 10.1016/j.bcp.2020.113947.
Xia Qin 1,  Longmiao Hu 1,  Shen-Nan Shi 2,  Xiaofei Chen 3,  Chunlin Zhuang 3,  Wen Zhang 4,  Siriporn Jitkaew 5,  Xiufeng Pang 6,  Jianqiang Yu 7,  Ye-Xiong Tan 8,  Hong-Yang Wang 9,  Zhenyu Cai 10
Affiliations

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.

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