State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
Eur J Med Chem. 2019 Nov 15;182:111633. doi: 10.1016/j.ejmech.2019.111633. Epub 2019 Aug 21.
Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
最近，选择性抑制 BET BD2 作为一种有前途的药物发现策略正在出现。尽管在这一领域取得了重大进展，但对选择性 BET BD2 抑制剂的系统研究仍然很少。在这项研究中，我们报告了一种有效的、选择性 BET BD2 抑制剂 BY27（47）的发现。我们的 47/BRD2 BD1 和 BD2 的高分辨率共晶结构显示，47 的三唑基团、水分子、BRD2 BD2 中的 H433 和 N429 建立了一个水桥氢键网络，这是导致观察到的选择性的原因。用 47 或 OTX015 处理 HepG2 细胞的 DNA 微阵列分析表明，BET BD2 选择性抑制剂和泛 BET 抑制剂之间的转录组影响存在差异。在 MV4-11 小鼠异种移植模型中，47 导致 67%的肿瘤生长抑制，并且在高剂量下比泛 BET 抑制剂 1 的毒性更小。我们得出结论，选择性 BET BD2 抑制剂的安全性得到改善，值得在 BET 相关疾病中进行进一步研究。
