Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation
Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation
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通过 PROTAC 介导的降解解决 NAMPT 的酶依赖性肿瘤促进功能
DOI：
10.1016/j.chembiol.2022.10.007
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发表时间：
2022
影响因子：
8.6
通讯作者：
Gaofeng Fan
中科院分区：
文献类型：
--
作者：
Xiaotong Zhu;Haixia Liu;Li Chen;Chenxu Wu;Xuesong Liu;Yong Cang;Biao Jiang;Xiaobao Yang;Gaofeng Fan
烟酰胺磷酸核糖基转移酶（NAMPT）的异常过表达已在多种肿瘤细胞中报道，并且是患者生存的不良预后因素。它在肿瘤细胞增殖中起重要作用，同时作为烟酰胺腺嘌呤二核苷酸（NAD+）合酶，并且出乎意料地作为几种肿瘤促进途径的细胞外信号分子。虽然以前调节NAMPT活性的努力仅限于酶抑制剂，在临床研究中成功率低，但蛋白质降解提供了同时破坏NAMPT酶活性和配体能力的可能性。在这里，我们报告了两个高度选择性的蛋白水解靶向嵌合体（PROTACs），促进NAMPT降解的cereblon依赖的方式的发展。两种PROTAC降解剂在对血液肿瘤细胞的杀伤作用方面均优于临床候选药物FK866。这些结果强调了应用PROTAC作为靶向具有多种肿瘤促进功能的蛋白质如NAMPT的上级策略的重要性和可行性，这是常规酶抑制剂不易实现的。
Aberrant overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been reported in a variety of tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell proliferation, acting concurrently as an nicotinamide adenine dinucleotide (NAD+) synthase and, unexpectedly, as an extracellular signaling molecule for several tumor-promoting pathways. Although previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers the possibility to simultaneously disrupt NAMPT's enzyme activity and ligand capabilities. Here we report the development of two highly selective proteolysis-targeting chimeras (PROTACs) that promote NAMPT degradation in a cereblon-dependent manner. 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 superior strategy for targeting proteins with multiple tumor-promoting functions like NAMPT, which is not easily achieved by conventional enzymatic inhibitors.