NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

作     者：Ying Wu Congying Pu Yixian Fu Guoqiang Dong Min Huang Chunquan Sheng Ying Wu;Congying Pu;Yixian Fu;Guoqiang Dong;Min Huang;Chunquan Sheng

作者机构：School of PharmacySecond Military Medical UniversityShanghai 200433China State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 201203China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第6期

页      面：2859-2868页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng 91957126 to Min Huang) the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng)。 

主　　题：NAMPT Non-enzymatic function eNAMPT Cancer MDSC PROTAC Tumor immunity Immunotherapy 

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(iNAMPT) 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.