BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with ΔT_m values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC₅₀ values of 0.78 and 0.87 μM. Furthermore, 11r (0.5−10 μM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5−10 μM) concentration-dependently blocked cell cycle in MV4-11 cells at G₀/G₁ phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.

BRD4 在基因转录调控中发挥着关键作用，并已被确定为癌症治疗的一个有吸引力的靶点。在这项研究中，我们通过用磺酰胺修饰3-乙基-苯并[d]异恶唑核心，设计了26种新化合物。大多数化合物表现出有效的 BRD4 结合活性，Δ T _m值超过 6 °C。获得了与BRD4(1)复合的11h和11r的两种晶体结构来表征结合模式。化合物11h和11r可有效结合BRD4(1)，并对MV4-11细胞显示出显着的抗增殖活性，IC ₅₀值为0.78和0.87 μM。此外， 11r (0.5−10 μM) 浓度依赖性地抑制 MV4-11 细胞中癌基因（包括 c-Myc 和 CDK6）的表达水平。此外， 11r (0.5−10 μM) 浓度依赖性地阻断 MV4-11 细胞中 G ₀ /G ₁期的细胞周期并诱导细胞凋亡。化合物11r可以作为进一步药物开发的新先导化合物。