NAMPT-targeting PROTAC promotes antitumor immunity <i>via</i> suppressing myeloid-derived suppressor cell expansion

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

doi:10.1016/j.apsb.2021.12.017

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

doi: 10.1016/j.apsb.2021.12.017

a. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China

基金项目:

This work was supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng

91957126 to Min Huang), and the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng).

详细信息

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383521004895/pdf?md5=75053477a15cb8c119793cef9a79cd40&pid=1-s2.0-S2211383521004895-main.pdf
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出版历程
- 收稿日期: 2021-09-28
- 修回日期: 2021-11-18
- 录用日期: 2021-11-29
- 网络出版日期: 2023-03-17

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

Ying Wu^a,
Congying Pu^b,
Yixian Fu^b,
Guoqiang Dong^{a
, ,},
Min Huang^{b
, ,},
Chunquan Sheng^{a
, ,}

a. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China

Funds:

This work was supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng

91957126 to Min Huang), and the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng).

摘要

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 non-enzymatic 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.
- NAMPT /
- Non-enzymatic function /
- eNAMPT /
- Cancer /
- MDSC /
- PROTAC /
- Tumor immunity /
- Immunotherapy
Abstract: 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 non-enzymatic 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.
- NAMPT /
- Non-enzymatic function /
- eNAMPT /
- Cancer /
- MDSC /
- PROTAC /
- Tumor immunity /
- Immunotherapy

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参考文献(32)

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

doi: 10.1016/j.apsb.2021.12.017

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

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

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

doi: 10.1016/j.apsb.2021.12.017

通讯作者: Guoqiang Dong,E-mail:dgq-81@163.com Min Huang,E-mail:mhuang@simm.ac.cn Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

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

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出版历程

目录

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn