Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer
Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer
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Y08060：一种用于治疗前列腺癌的选择性 BET 抑制剂
DOI：
10.1021/acsmedchemlett.8b00003
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发表时间：
2018
影响因子：
4.2
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Xiang Quping;Zhang Yan;Li Jiaguo;Xue Xiaoqian;Wang Chao;Song Ming;Zhang Cheng;Wang Rui;Li Chenchang;Wu Chun;Zhou Yulai;Yang Xiaohong;Li Guohui;Ding Ke;Xu Yong
前列腺癌是一种常见的癌症，也是癌症相关死亡的主要原因。溴结构域和额外末端结构域（BET）家族蛋白已成为治疗去势抵抗性前列腺癌的潜在治疗靶点。设计并合成了一系列2,2-二甲基- 2h -苯并[b][1,4]恶嗪-3(4H)- 1衍生物，作为选择性含溴结构域蛋白4 （BRD4）抑制剂。这些化合物能有效抑制BRD4(1)，其ic50值为纳摩尔，并且对大多数非bet亚家族成员具有高选择性。其中一个代表性化合物36（Y08060）有效抑制前列腺癌细胞系中雄激素受体（AR）、AR调节基因和MYC的细胞生长、集落形成和表达。在体内研究中，36显示出良好的PK谱，具有较高的口服生物利用度（61.54%），是进一步开发前列腺癌药物的有希望的先导化合物。
Prostate cancer is a commonly diagnosed cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate cancer. A series of 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50values and exhibit high selectivity over most non-BET subfamily members. One of the representative compounds36(Y08060) effectively suppresses cell growth, colony formation, and expression of androgen receptor (AR), AR regulated genes, and MYC in prostate cancer cell lines. Inin vivostudies,36demonstrates a good PK profile with high oral bioavailability (61.54%) and is a promising lead compound for further prostate cancer drug development.