NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion
文献类型：期刊论文
| 作者 | Wu, Ying1; Pu, Congying2; Fu, Yixian2; Dong, Guoqiang1; Huang, Min2 ; Sheng, Chunquan1
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| 刊名 | ACTA PHARMACEUTICA SINICA B
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| 出版日期 | 2022-06 |
| 卷号 | 12期号:6页码:2859-2868 |
| ISSN号 | 2211-3835 |
| 关键词 | NAMPT Non-enzymatic function eNAMPT Cancer MDSC PROTAC Tumor immunity Immunotherapy |
| DOI | 10.1016/j.apsb.2021.12.017 |
| 文献子类 | Article |
| 英文摘要 | Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene nonenzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iN-AMPT) via the ubiquitin-proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. |
| WOS关键词 | EXTRACELLULAR NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE ; NAD(+) ; PATHWAYS ; THERAPY |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| WOS记录号 | WOS:000834839900006 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309339]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Dong, Guoqiang; Huang, Min; Sheng, Chunquan |
| 作者单位 | 1.Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China; 2.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Ying,Pu, Congying,Fu, Yixian,et al. NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion[J]. ACTA PHARMACEUTICA SINICA B,2022,12(6):2859-2868. |
| APA | Wu, Ying,Pu, Congying,Fu, Yixian,Dong, Guoqiang,Huang, Min,&Sheng, Chunquan.(2022).NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion.ACTA PHARMACEUTICA SINICA B,12(6),2859-2868. |
| MLA | Wu, Ying,et al."NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion".ACTA PHARMACEUTICA SINICA B 12.6(2022):2859-2868. |
入库方式： OAI收割
来源：上海药物研究所
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