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 NAMPT’s 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.

中文翻译：

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通过 PROTAC 介导的降解解决 NAMPT 的非酶促肿瘤促进功能

NAD ⁺合成挽救途径的限速酶NAMPT 在多种肿瘤细胞中异常过度表达，是患者生存的不良预后因素。NAMPT 在肿瘤细胞增殖中起主要作用，同时作为 NAD ⁺合酶，出人意料的是，它是几种促肿瘤信号通路的细胞外配体。虽然之前调节 NAMPT 活性的努力仅限于在临床研究中成功率较低的酶抑制剂，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，我们报告了两种高选择性 NAMPT 靶向蛋白水解靶向嵌合体 (PROTAC) 的开发，其在多种肿瘤细胞系中以脑依赖性方式促进快速有效的 NAMPT 降解。值得注意的是，这两种 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物 FK866。这些结果强调了应用 PROTAC 作为靶向具有双重肿瘤促进功能的 NAMPT 等蛋白质的更好策略的重要性和可行性，