Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3
文献类型：期刊论文
| 作者 | Chen, Xiaofei3,4,5; Ren, Yibin3; Qin, Xia3,4; Hu, Longmiao3,4; Fu, Jing3,4; Cai, Zhenyu3,4; Wang, Hong-yang2,3,4; Zhuang, Chunlin5; Miao, Zhenyuan5; Chai, Yifeng5 |
| 刊名 | BRITISH JOURNAL OF PHARMACOLOGY
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| 出版日期 | 2019 |
| 卷号 | 176期号:12页码:2095-2108 |
| 关键词 | Post-translational modification myristoylation site prediction modified glycine residue extreme learning machine minimum redundancy maximum relevance incremental feature selection |
| ISSN号 | 0007-1188 |
| DOI | 10.1111/bph.14653 |
| 文献子类 | Article |
| 英文摘要 | Background and Purpose Necroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan-Raf inhibitor TAK-632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK-632 by targeting RIPK1 and RIPK3. Experimental Approach Cell viability was measured by MTT, propidium staining, or CellTiter-Glo luminescent assays. Effects of TAK-632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK-632 were identified by a drug affinity responsive target stability assay and a pull-down assay with biotinylated TAK-632. A mouse model of TNF-alpha-induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK-632 in protecting against necroptosis-associated inflammation in vivo. Key Results TAK-632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK-632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK-632 alleviated TNF-induced SIRS. Furthermore, we performed a structure-activity relationship analysis of TAK-632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3. Conclusions and Implications TAK-632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3. |
| 学科主题 | Pharmacology & Pharmacy |
| WOS关键词 | MIXED LINEAGE KINASE ; DOMAIN-LIKE PROTEIN ; CONCISE GUIDE ; DISCOVERY ; NECROSIS ; PHOSPHORYLATION ; DOWNSTREAM ; MECHANISMS ; DESIGN ; DEATH |
| 语种 | 英语 |
| WOS记录号 | WOS:000469046000022 |
| 出版者 | WILEY |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/1000]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab,Inst Nutr Sci, Shanghai, Peoples R China; 2.Fudan Univ, Canc Inst, Shanghai Canc Ctr, Shanghai, Peoples R China, 3.Second Mil Med Univ, Natl Ctr Liver Canc, Shanghai, Peoples R China; 4.Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Int Cooperat Lab Signal Transduct, Shanghai, Peoples R China; 5.Second Mil Med Univ, Sch Pharm, 325 Guohe Rd, Shanghai 200433, Peoples R China; 6.Ningxia Med Univ, Sch Pharm, Yinchuan, Peoples R China; 7.NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA; |
| 推荐引用方式 GB/T 7714 | Chen, Xiaofei,Ren, Yibin,Qin, Xia,et al. Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3[J]. BRITISH JOURNAL OF PHARMACOLOGY,2019,176(12):2095-2108. |
| APA | Chen, Xiaofei.,Ren, Yibin.,Qin, Xia.,Hu, Longmiao.,Fu, Jing.,...&,.(2019).Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3.BRITISH JOURNAL OF PHARMACOLOGY,176(12),2095-2108. |
| MLA | Chen, Xiaofei,et al."Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3".BRITISH JOURNAL OF PHARMACOLOGY 176.12(2019):2095-2108. |
入库方式： OAI收割
来源：上海营养与健康研究所
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