In this new article publication from Acta Pharmaceutica Sinica B, authors Ying Wu, Congying Pu, Yixian Fu, Guoqiang Dong, Min Huang and Chunquan Sheng from Second Military Medical University, Shanghai, China and University of Chinese Academy of Sciences, Shanghai, China discuss how NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion.
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.
In this article the authors demonstrate 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, the 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.
Article reference: Ying Wu, Congying Pu, Yixian Fu, Guoqiang Dong, Min Huang, Chunquan Sheng, NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloi d-derived suppressor cell expansion, Acta Pharmaceutica Sinica B, Volume 12, Issue 6, 2022, Pages 2859-2868, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2021.12.017
Keywords: NAMPT, Non-enzymatic function, eNAMPT, Cancer, MDSC, PROTAC, Tumor immunity, Immunotherapy
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383521004895-ga1_lrg.jpg
eNAMPT secreted from tumor cells suppresses antitumor immunity by promoting the expansion of tumor infiltrating MDSCs. NAMPT-specific PROTAC A7 directly degrades intracellular NAMPT, which in turn downregulates eNAMPT and promotes antitumor immunity.
# # # # # #
The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
For more information please visit https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/
Editorial Board: https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/editorial-board
APSB is available on ScienceDirect (https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b).
Submissions to APSB may be made using Editorial Manager® (https://www.editorialmanager.com/apsb/default.aspx).
CiteScore: 12.5
Impact Factor: 11.614
JIF without self-citation: 10.746
ISSN 2211-3835
# # # # #