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Abstract：
The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.
摘要：
乳腺癌的恶性构成了全球性的挑战，现有的治疗方法往往达不到预期的疗效。广泛的研究强调了靶向烟酰胺腺嘌呤二核苷酸（NAD）代谢的有效性，对癌细胞存活和生长至关重要的关键分子，作为一种有前途的抗癌策略。在哺乳动物细胞内，维持最佳NAD浓度依赖于两种关键酶，即烟酰胺磷酸核糖基转移酶(NAMPT)和聚(ADP-核糖)聚合物1(PARP1)。最近的研究强调了结合NAMPT抑制剂和PARP1抑制剂以增强治疗结果的潜在益处。特别是在乳腺癌中。在这项研究中,我们设计并合成了11种新型NAMPT/PARP1双靶点抑制剂。其中,化合物DDY02对NAMPT和PARP1均表现出可接受的抑制活性，IC50值为0.01和0.05μM，分别。此外，体外评估显示，用DDY02处理导致增殖抑制，NAD耗尽,DNA损伤,凋亡，和在MDA-MB-468细胞中的迁移抑制。这些结果通过抑制NAMPT和PARP1靶向NAD代谢，将DDY02作为乳腺癌治疗发展的有希望的先导化合物。
