Proteins of the bromodomain and extra-terminal (BET) family are epigenetics “readers” and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.

中文翻译：

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发现QCA570是一种有针对性的高效蛋白水解靶定嵌合蛋白（PROTAC）降解的Bromodomain和末端（BET）蛋白，能够诱导完全持久的肿瘤消退。

bromodomain和Extra-terminal（BET）家族的蛋白质是表观遗传学“阅读器”，是癌症和其他人类疾病的有希望的治疗靶标。我们在本文中描述了作为新一类BET抑制剂的[1,4]奥氮平的结构导向设计，以及我们随后设计，合成和评估靶向蛋白水解的嵌合（PROTAC）小分子BET降解剂的过程。我们的努力已导致发现极有效的BET降解剂，例如QCA570，它即使在低皮摩尔浓度下也能有效诱导BET蛋白降解并抑制人急性白血病细胞系中的细胞生长。QCA570在耐受良好的剂量时间表下在小鼠白血病异种移植模型中实现了完整而持久的肿瘤消退。QCA570是迄今为止报道的最有效，最有效的BET降解剂。