Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC₅₀ value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC₅₀ value of 0.42 μM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.

含溴结构域的蛋白质4（BRD4）是癌症中的关键表观遗传调节剂，靶向BRD4的抑制剂具有强大的抗癌活性。通过用N-甲基噻唑烷酮杂环取代BRD4抑制剂I-BET-762的甲基三唑环，设计并合成了15种新型BRD4抑制剂。化合物13f具有疏水性乙酰基环戊基侧链，在BRD4-BD1抑制试验中显示出最有效的BRD4抑制活性（IC ₅₀值为110 nM），它还显着抑制了高BRD4水平的MV-4-11细胞的增殖（ IC ₅₀值为0.42μM）。此外，化合物13f具有强大的促凋亡和G0 / G1周期阻滞活性通过流式细胞术指示。作为BRD4的下游蛋白，通过化合物13f处理，c-Myc的表达呈剂量依赖性，其表达明显降低。所有发现均支持该新型化合物13f为开发有效的BRD4抑制剂提供了前景。