近年来，人们对在癌症治疗中使用蛋白水解靶向嵌合体（PROTAC）的兴趣有所增加。靶向溴结构域和额外末端结构域 (BET) 蛋白，尤其是含溴结构域蛋白 4 (BRD4)，已显示出对基底样乳腺癌 (BLBC) 的抑制作用。然而，BRD4 PROTAC 的生物利用度受到其非选择性生物降解性和低肿瘤靶向能力的限制。我们证明，6b (BRD4 PROTAC) 通过靶向 BRD4（而非 BRD2 和 BRD3）来抑制 BLBC 细胞生长，从而实现 cereblon (CRBN) 介导的泛素化和蛋白酶体降解。化合物 6b 还抑制 Krüppel 样因子 5 (KLF5) 转录因子的表达，Krüppel 样因子 5 (KLF5) 是 BLBC 中的一种关键癌蛋白，由 BRD4 介导的超级增强子控制。此外，6b 在异种移植小鼠模型中抑制 HCC1806 肿瘤生长。 6b 和 KLF5 抑制剂的组合对 BLBC 显示出相加效应。这些结果表明，BRD4 特异性 PROTAC 可以通过下调 KLF5 有效抑制 BLBC，并且 6b 有潜力作为 BLBC 的新型治疗药物。© 2024。作者。

Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC.© 2024. The Author(s).