Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI:10.1016/j.bmcl.2025.130117

Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang

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Abstract

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 (IC₅₀ = 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.

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发现双PARP/NAMPT抑制剂治疗BRCA野生型三阴性乳腺癌。

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）已被证明通过合成致死率对乳腺癌易感性（BRCA）野生型三阴性乳腺癌（TNBC）具有协同作用，这可能会拓宽PARP抑制剂的临床应用范围。在此，我们报告了通过药效团连接方法发现的双重PARP/NAMPT抑制剂。先导化合物13j对PARP1和NAMPT均具有较强的抑制活性（IC50分别为 = 0.8和18 nM），可在亚微摩尔水平上有效抑制野生型BRCA的TNBC MDA-MB-231细胞的增殖。机械上，13j破坏同源重组修复（HRR）途径，导致DNA双链断裂（DSBs）积累，最终诱导凋亡细胞死亡。此外，该化合物对MDA-MB-231细胞的迁移具有较强的抑制作用。本研究表明，化合物13j是开发更好的PARP/NAMPT抑制剂治疗TNBC野生型BRCA的有希望的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.