Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation

doi:10.1101/2021.09.13.460066

	Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation
	Zhu, X.1 ; Liu, H.2,3,4 ; Chen, L.1; Cang, Y.1 ; Jiang, B.5; Yang, X.6; Fan, G.1
	2021-09-13
状态	已发表
摘要	The rate-limiting enzyme of salvage pathway for NAD⁺ synthesis, NAMPT, is aberrantly overexpressed in a variety of tumor cells and is a poor prognosis factor for patient survival. NAMPT plays a major role in tumor cell proliferation, acting concurrently as an NAD+ synthase and unexpectedly, an extracellular ligand for several tumor-promoting signaling pathways. While previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously disrupt NAMPTs enzyme activity and ligand capabilities. Here, we report the development of two highly selective NAMPT-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent NAMPT degradation in a cereblon-dependent manner in multiple tumor cell lines. Notably, both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a better strategy for targeting proteins like NAMPT with dual tumor-promoting functions, which are not easily achieved by conventional enzymatic inhibitors.
语种	英语
DOI	10.1101/2021.09.13.460066
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:9588778
WOS类目	Biochemistry & Molecular Biology
资助项目	Ministry of Science and Technology of China["19SG55","32070776","2018YFC1004603","19JC1413800"] ; National Natural Science Foundation of China[31872831]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/348533
专题	生命科学与技术学院物质科学与技术学院生命科学与技术学院_PI研究组_范高峰组免疫化学研究所生命科学与技术学院_PI研究组_仓勇组物质科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Jiang, B.; Yang, X.; Fan, G.
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China 3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, Shanghai 200032, Peoples R China 6.Gluetacs Therapeut Shanghai Co Ltd, Zhangjiang Hitech Pk, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Zhu, X.,Liu, H.,Chen, L.,et al. Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation. 2021.