Zhao Leilei, Yang Yifei, Guo Yahui, Yang Lingyun, Zhang Jian, Zhou Jinpei, Zhang Huibin
Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Med Chem. 2017 Apr 15;25(8):2482-2490. doi: 10.1016/j.bmc.2017.03.008. Epub 2017 Mar 7.
BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC values of 130 and 76nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 10j potently inhibited cell proliferation in BRD4-sensitive cell lines HL-60 and MV4-11 with IC value of 0.57 and 0.18μM respectively. Activity on BRD4-independent K562 cell was weaker than on BRD4-sensitive lines. Overall, these results suggest that compound 10j is a potential BRD4 inhibitor deserving further investigation for cancer treatment.
由于BRD4在基因转录调控中发挥重要作用，它成为一个有吸引力的抗肿瘤靶点。在本文中，我们合成了一系列7-甲基咪唑并[1,5-a]吡嗪-8(7H)-酮衍生物作为有效的BRD4抑制剂，并评估了它们在体外的BRD4抑制活性以及对肿瘤细胞的抗增殖作用。令人满意的是，化合物10j对BRD4(1)和BRD4(2)表现出强大的抑制效力，IC值分别为130和76nM。进行了对接研究以解释构效关系。此外，化合物10j在BRD4敏感细胞系HL-60和MV4-11中有效抑制细胞增殖，IC值分别为0.57和0.18μM。对不依赖BRD4的K562细胞的活性比对BRD4敏感细胞系的活性弱。总体而言，这些结果表明化合物10j是一种潜在的BRD4抑制剂，值得进一步研究用于癌症治疗。
