BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 μM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 μM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

中文翻译：

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4-(3-(3,5-二甲基异恶唑-4-基)苯甲基)酞嗪-1(2H)-酮衍生物的设计、合成和评估：具有抗乳腺癌活性的有效 BRD4 抑制剂


BRD4抑制剂在癌症治疗中表现出巨大的潜力。然而，它们对乳腺癌的治疗效果因乳腺癌亚型而异，特别是在 TNBC 的治疗中。在本研究中，我们设计并合成了94种4-(3-(3,5-二甲基异恶唑-4-基)苯甲基)酞嗪-1(2H)-酮衍生物，以评估它们对BRD4的抑制活性。值得注意的是，化合物 DDT26 对 BRD4 表现出最有效的抑制作用，IC 50值为 0.237 ± 0.093 μM。 DDT26 对 TNBC 细胞系和 MCF-7 细胞具有显着的抗增殖活性。有趣的是，DDT26 的二氮杂萘酮部分模仿了 PAPR1 底物，导致 DDT26 通过 IC 对 PARP1 显示出中等的抑制作用50值为 4.289 ± 1.807 μM。此外，DDT26 可调节 c-MYC 和 γ-H2AX 的表达，诱导 DNA 损伤，抑制细胞迁移和集落形成，并将 MCF-7 细胞的细胞周期阻滞在 G1 期。我们的研究结果为开发针对 BRD4 的有效抗乳腺癌药物提供了潜在的先导化合物。