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 IC₅₀ values and exhibit high selectivity over most non-BET subfamily members. One of the representative compounds 36 (Y08060) effectively suppresses cell growth, colony formation, and expression of androgen receptor (AR), AR regulated genes, and MYC in prostate cancer cell lines. In in vivo studies, 36 demonstrates a good PK profile with high oral bioavailability (61.54%) and is a promising lead compound for further prostate cancer drug development.

中文翻译：

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Y08060：治疗前列腺癌的选择性BET抑制剂

前列腺癌是一种常见的癌症，是与癌症相关的死亡的主要原因。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标。设计并合成了一系列2,2-二甲基-2 H-苯并[ b ] [1,4]恶嗪-3（4 H）-one衍生物，作为含溴结构域的选择性蛋白4（BRD4）抑制剂。这些化合物有效抑制BRD4（1）的纳摩尔IC ₅₀值，并且对大多数非BET亚家族成员显示出高选择性。代表性化合物之一36（Y08060）有效抑制前列腺癌细胞系中的细胞生长，集落形成以及雄激素受体（AR），AR调控基因和MYC的表达。在体内研究中，36表现出良好的PK分布和较高的口服生物利用度（61.54％），是用于进一步开发前列腺癌药物的有希望的先导化合物。