Proteolysis-targeting chimera (PROTAC) is emerging as a promising technology in targeted protein degradation and drug discovery. However, there is still a lack of effective chemical tools to real-time detect and track the protein degradation. Herein, the first fluorescent and theranostic PROTACs were designed for imaging the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells. Compound B4 was proven to be an environmentally sensitive fluorescent PROTAC, which efficiently degraded NAMPT (DC₅₀ = 8.4 nM) and enabled the visualization of degradation in A2780 cells. As a theranostic agent, PROTAC B4 led to significant reduction of nicotinamide adenine dinucleotide (NAD⁺) and exerted potent antitumor activities both in vitro and in vivo. Collectively, this proof-of-concept study provides a new strategy for the real-time visualization of the process of protein degradation and the improvement of diagnosis and therapeutic efficacy of PROTACs.

中文翻译：

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使蛋白质降解可见：用于检测和降解 NAMPT 的治疗诊断 PROTAC 的发现

蛋白水解靶向嵌合体 (PROTAC) 正在成为靶向蛋白质降解和药物发现领域的一项有前景的技术。然而，仍然缺乏有效的化学工具来实时检测和跟踪蛋白质降解。在此，第一个荧光和治疗诊断 PROTAC 被设计用于对活细胞中烟酰胺磷酸核糖转移酶 (NAMPT) 的降解进行成像。化合物B4被证明是一种环境敏感的荧光 PROTAC，可有效降解 NAMPT (DC ₅₀ = 8.4 nM)，并实现 A2780 细胞中降解的可视化。作为一种治疗诊断剂，PROTAC B4可显着减少烟酰胺腺嘌呤二核苷酸 (NAD ⁺ )，并在体外和体内发挥有效的抗肿瘤活性。总的来说，这项概念验证研究为蛋白质降解过程的实时可视化和提高 PROTAC 的诊断和治疗效果提供了一种新策略。