背景：利用蛋白质对之间的合成致死（SL）关系已成为开发抗癌药物的重要途径。烟酰胺磷酸核糖基转移酶 (NAMPT) 是 NAD 挽救途径的限速酶，与 NAD Preiss-Handler 途径中的关键酶烟酸磷酸核糖基转移酶 (NAPRT) 具有 SL 关系。 NAMPT 抑制剂不仅具有作为一种有前景的癌症治疗方法的临床潜力，而且还具有作为预防化疗引起的周围神经病变 (CIPN) 的一种手段的临床潜力。然而，由于NAD对于正常细胞至关重要，因此NAMPT抑制剂的临床使用具有挑战性。本研究旨在鉴定一种新型 NAMPT 抑制剂，该抑制剂对 NAPRT 缺陷的癌细胞具有增强的选择性细胞毒性，并且在缓解 CIPN 方面具有显着功效。方法：我们首先在一组肺癌细胞系中进行药物衍生物筛选，以选择一种在 NAPRT 阴性和阳性癌细胞系之间具有最宽治疗窗的药物。对 A4276 和其他 NAMPT 抑制剂进行体外和体内比较分析，以评估 A4276 的 NAPRT 阴性癌细胞选择性和潜在的独特 NAMPT 抑制机制。对患者来源的肿瘤转录组数据和各种癌细胞系中的蛋白质水平进行分析，以确认各种癌症类型中 NAPRT 耗竭与上皮间质转化 (EMT) 样特征之间的相关性。最后，在体外和体内检查了 A4276 对轴突保护和 CIPN 治疗的功效。结果：生物标志物驱动的表型筛选发现 A4276 与 NAPRT 阳性癌细胞和正常细胞相比，对 NAPRT 阴性癌细胞具有显着的选择性。 A4276 对 NAPRT 阴性细胞的细胞毒作用是通过其与 NAMPT 的直接结合来实现的，以最佳和平衡的水平抑制其酶功能，从而允许 NAPRT 阳性细胞通过 NAPRT 依赖性 NAD 合成而存活。 NAPRT 缺陷是对 A4276 反应的生物标志物，也是各种肿瘤类型中 EMT 亚型癌症的指标。值得注意的是，A4276 通过降低 NMN 与 NAD 的比率，比其他 NAMPT 抑制剂更有效地保护轴突免受华勒变性。结论：这项研究表明，A4276 选择性地靶向 NAPRT 缺陷的 EMT 亚型癌细胞，并预防化疗引起的周围神经病变，凸显了其作为一种有前途的抗癌药物用于癌症单一疗法或与常规化疗联合治疗的潜力。 © 作者（s）。

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.© The author(s).