Mao Jie, Wang Kaizhen, Tong Jun, Zhang Wanheng, Shen Guoqing, Wang Dexiang, Liao Zepeng, Zhang Zhiyi, Miao Qi, Jiang Sheng, Zhang Kuojun
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009 China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009 China.
Bioorg Med Chem Lett. 2025 May 1;120:130117. doi: 10.1016/j.bmcl.2025.130117. Epub 2025 Jan 30.
Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound 13j with potent inhibitory activity against both PARP1 and NAMPT (IC = 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, 13j disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound 13j is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.
已证明同时抑制聚（ADP - 核糖）聚合酶（PARP）和烟酰胺磷酸核糖基转移酶（NAMPT）通过合成致死作用对乳腺癌易感（BRCA）野生型三阴性乳腺癌（TNBC）具有协同疗效，这一点可用于拓展PARP抑制剂的临床应用。在此，我们报告通过药效团连接方法发现双PARP/NAMPT抑制剂。先导化合物13j对PARP1和NAMPT均具有强效抑制活性（IC分别为0.8和18 nM），能在亚微摩尔水平有效抑制野生型BRCA的TNBC MDA - MB - 231细胞增殖。机制上，13j破坏同源重组修复（HRR）途径，导致DNA双链断裂（DSB）积累，最终诱导凋亡性细胞死亡。此外，该化合物对MDA - MB - 231细胞的迁移也表现出强效抑制作用。本研究表明化合物13j是开发更好的PARP/NAMPT抑制剂以治疗野生型BRCA的TNBC的有前景的先导化合物。
