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Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-08-21 , DOI: 10.1016/j.ejmech.2019.111633 Deheng Chen 1 , Tian Lu 2 , Ziqin Yan 3 , Wenchao Lu 1 , Feilong Zhou 3 , Xilin Lyu 3 , Biling Xu 4 , Hualiang Jiang 3 , Kaixian Chen 2 , Cheng Luo 2 , Yujun Zhao 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-08-21 , DOI: 10.1016/j.ejmech.2019.111633 Deheng Chen 1 , Tian Lu 2 , Ziqin Yan 3 , Wenchao Lu 1 , Feilong Zhou 3 , Xilin Lyu 3 , Biling Xu 4 , Hualiang Jiang 3 , Kaixian Chen 2 , Cheng Luo 2 , Yujun Zhao 1
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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.
中文翻译：
作为BET蛋白第二溴结构域的选择性抑制剂的BY27的发现，结构见解和生物活性。
最近，对BET BD2的选择性抑制正在成为一种有前途的药物发现策略。尽管在该领域取得了重大进展，但选择性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且选择性的BET BD2抑制剂BY27的发现（47）。我们的高分辨率共晶体结构47 / BRD2 BD1和BD2显示，BRD2 BD2中的47，水分子，H433和N429的三唑基建立了水桥H键网络，这是观察到的选择性的原因。用47或OTX015处理的HepG2细胞的DNA微阵列分析表明，BET BD2选择性抑制剂和pan BET抑制剂之间的转录组影响差异。在MV4-11小鼠异种移植模型中，47在大剂量时可引起67％的肿瘤生长抑制，且毒性比pan BET抑制剂1低。我们得出结论，选择性BET BD2抑制剂的改善的安全性值得在BET相关疾病中进行进一步的研究。
更新日期：2019-08-21
中文翻译：
作为BET蛋白第二溴结构域的选择性抑制剂的BY27的发现，结构见解和生物活性。
最近，对BET BD2的选择性抑制正在成为一种有前途的药物发现策略。尽管在该领域取得了重大进展，但选择性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且选择性的BET BD2抑制剂BY27的发现（47）。我们的高分辨率共晶体结构47 / BRD2 BD1和BD2显示，BRD2 BD2中的47，水分子，H433和N429的三唑基建立了水桥H键网络，这是观察到的选择性的原因。用47或OTX015处理的HepG2细胞的DNA微阵列分析表明，BET BD2选择性抑制剂和pan BET抑制剂之间的转录组影响差异。在MV4-11小鼠异种移植模型中，47在大剂量时可引起67％的肿瘤生长抑制，且毒性比pan BET抑制剂1低。我们得出结论，选择性BET BD2抑制剂的改善的安全性值得在BET相关疾病中进行进一步的研究。
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