Nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic target for treating select cancers. There are two forms of NAMPT: intracellular NAMPT (iNAMPT, the rate-limiting enzyme in the mammalian NAD⁺ main synthetic pathway) and extracellular NAMPT (eNAMPT, a cytokine with protumorigenic function). Reported NAMPT inhibitors only inhibit iNAMPT and show potent activities in preclinical studies. Unfortunately, they failed to show efficacy due to futility and toxicity. We developed a series of FK866-based NAMPT-targeting PROTACs and identified LYP-8 as a potent and effective NAMPT degrader that simultaneously diminished iNAMPT and eNAMPT. Importantly, LYP-8 demonstrated superior efficacy and safety in mice when compared to the clinical candidate, FK866. This study highlights the importance and feasibility of applying PROTACs as a superior strategy for interfering with both the enzymatic function of NAMPT (iNAMPT) and nonenzymatic function of NAMPT (eNAMPT), which is difficult to achieve with conventional NAMPT inhibitors.

中文翻译：

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基于 FK866 的阻断烟酰胺磷酸核糖基转移酶非酶功能的降解剂的设计


烟酰胺磷酸核糖转移酶 (NAMPT) 是治疗特定癌症的一个有吸引力的治疗靶点。 NAMPT有两种形式：细胞内NAMPT（iNAMPT，哺乳动物NAD ⁺ 主要合成途径中的限速酶）和细胞外NAMPT（eNAMPT，具有促肿瘤功能的细胞因子）。报道的 NAMPT 抑制剂仅抑制 iNAMPT，并在临床前研究中显示出有效的活性。不幸的是，由于无效和毒性，它们未能显示出功效。我们开发了一系列基于 FK866 的 NAMPT 靶向 PROTAC，并确定 LYP-8 是一种强效且有效的 NAMPT 降解剂，可同时减少 iNAMPT 和 eNAMPT。重要的是，与临床候选药物 FK866 相比，LYP-8 在小鼠中表现出卓越的功效和安全性。这项研究强调了应用 PROTAC 作为干扰 NAMPT 酶促功能 (iNAMPT) 和 NAMPT 非酶促功能 (eNAMPT) 的优越策略的重要性和可行性，这是传统 NAMPT 抑制剂难以实现的。