Rong Juan, Feng Zhan-Zhan, Shi Yao-Jie, Ren Jing, Xu Ying, Wang Ning-Yu, Xue Qiang, Liu Kun-Lin, Zhou Shu-Yan, Wei Wei, Yu Luo-Ting
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Bioorg Med Chem Lett. 2019 Oct 1;29(19):126577. doi: 10.1016/j.bmcl.2019.07.036. Epub 2019 Jul 25.
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC values of 0.55 μM, 0.86 μM and 0.80 μM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC values of 0.19 μM, 0.32 μM and 0.12 μM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.
含溴结构域蛋白4（BRD4）是溴结构域和额外末端（BET）家族的成员，已被认为是几种癌症中靶向基因转录治疗的有吸引力的候选靶点。在本研究中，设计、合成并评估了两种新型化合物作为BRD4抑制剂。其中，吡啶酮衍生物对BRD4蛋白和人白血病细胞系MV4 - 11更有效。其中，化合物11d、11e和11f是最具潜力的化合物，对BRD4的IC值分别为0.55μM、0.86μM和0.80μM，并对MV4 - 11细胞表现出显著的抗增殖活性，IC值分别为0.19μM、0.32μM和0.12μM。此外，在蛋白质免疫印迹分析中，化合物11e诱导C - Myc下调，C - Myc是BRD4的一个重要下游基因。细胞周期分析试验还表明，化合物11e可将MV4 - 11细胞阻滞在G0/G1期。综上所述，我们的结果表明化合物11e及其衍生物是一类新型的具有结构潜力的BRD4抑制剂，可作为进一步探索的先导化合物。
