Bromodomain‐containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI‐2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4‐difluoro‐1‐methyl‐N,6‐diphenyl‐5,6‐dihydro‐4H‐pyrimido[4,5‐b] [1,2,4] triazolo[4,3‐d] [1,4] diazepine‐8‐amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4‐BD1 (IC₅₀ value of 0.42 μM) in the BRD4‐BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4‐11 cells (IC₅₀ value of 0.51 μM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4‐11 leukemia cells effectively, and downregulated the expression of c‐Myc in a dose‐dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.

中文翻译：

---

新型 4,4-difluoro-1-methyl-N, 6-diphenyl-5, 6-dihydro-4H-pyrimido [4, 5-b] [1, 2, 4] 三唑并 [1, 2, 4] 的设计、合成和生物学评价4, 3-d] [1, 4] diazepin-8-amine 衍生物作为潜在的 BRD4 抑制剂

含溴结构域蛋白4（BRD4）在癌症中起着极其重要的生理作用，BRD4抑制剂可以有效抑制肿瘤细胞的增殖。以 BI-2536（PLK1 和 BRD4 抑制剂）为先导化合物，16 种新型 BRD4 抑制剂与 4,4-difluoro-1-methyl- N ,6-diphenyl-5,6-dihydro-4 H - pyrimido[4 ,5- b ][1,2,4]三唑并[4,3- d ][1,4]二氮杂-8-胺结构的设计和合成。在目标化合物中，化合物15h在 BRD4-BD1 抑制活性测定中表现出对 BRD4-BD1 的显着抑制（IC ₅₀值为 0.42 μM）。此外，细胞生长抑制试验表明，化合物15h有效抑制 MV4-11 细胞的增殖（IC ₅₀值为 0.51 μM）。此外，化合物15h有效诱导MV4-11白血病细胞凋亡和G0/G1周期阻滞，并以剂量​​依赖性方式下调c-Myc的表达。综上所述，最佳化合物15h有望成为进一步研究的临床治疗药物。