Wang Kaizhen, Ye Ke, Zhang Xiangyu, Wang Tianyu, Qi Zhihao, Wang Youjun, Jiang Sheng, Zhang Kuojun
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2023 Jan 12;66(1):1027-1047. doi: 10.1021/acs.jmedchem.2c01954. Epub 2023 Jan 3.
Depleting NAD by blocking its biosynthesis has emerged as an attractive anticancer strategy. Simultaneous blockade of NAD production from the salvage and synthesis pathways by targeting NAMPT and IDO1 could achieve more effective NAD reduction and, subsequently, more robust antitumor efficacy. Herein, we report the discovery of the first series of dual NAMPT and IDO1 inhibitors according to multitarget drug rationales. Compound has good and balanced inhibitory potencies against NAMPT and IDO1, and significantly inhibits both proliferation and migration of a NSCLC cell line resistant to taxol and FK866 (A549/R cells). Compound also displays potent antitumor efficacy in A549/R xenograft mouse models with no significant toxicity. Moreover, this compound enhances the susceptibility of A549/R cells to taxol and . This work provides an efficient approach to targeting NAD metabolism in the area of cancer therapy, especially in the context of drug resistance.
通过阻断烟酰胺腺嘌呤二核苷酸（NAD）的生物合成来消耗NAD已成为一种有吸引力的抗癌策略。通过靶向烟酰胺磷酸核糖转移酶（NAMPT）和吲哚胺2,3-双加氧酶1（IDO1）同时阻断补救途径和合成途径中的NAD生成，可以实现更有效的NAD降低，进而产生更强的抗肿瘤疗效。在此，我们根据多靶点药物原理报告了首个系列的NAMPT和IDO1双重抑制剂的发现。化合物对NAMPT和IDO1具有良好且平衡的抑制效力，并显著抑制对紫杉醇和FK866耐药的非小细胞肺癌细胞系（A549/R细胞）的增殖和迁移。化合物在A549/R异种移植小鼠模型中也显示出强效的抗肿瘤疗效且无明显毒性。此外，该化合物增强了A549/R细胞对紫杉醇和[此处原文缺失一种药物名称]的敏感性。这项工作为癌症治疗领域，尤其是在耐药背景下靶向NAD代谢提供了一种有效方法。
