Pathology Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
Oncogene. 2024 Sep;43(39):2914-2926. doi: 10.1038/s41388-024-03121-1. Epub 2024 Aug 20.
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.
近年来，人们对利用蛋白水解靶向嵌合体（PROTACs）治疗癌症的兴趣日益增加。靶向溴结构域和末端结构域（BET）蛋白，特别是含有溴结构域的蛋白 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）通过针对 cereblon（CRBN）介导的泛素化和蛋白酶体降解来抑制 BLBC 细胞生长，而不针对 BRD2 和 BRD3。化合物 6b 还抑制了 BLBC 中关键癌蛋白 Krüppel 样因子 5（KLF5）转录因子的表达，该转录因子受 BRD4 介导的超级增强子控制。此外，6b 抑制了异种移植小鼠模型中 HCC1806 肿瘤的生长。6b 与 KLF5 抑制剂的联合使用对 BLBC 具有相加作用。这些结果表明，BRD4 特异性 PROTAC 可通过下调 KLF5 有效抑制 BLBC，并且 6b 具有作为 BLBC 新型治疗药物的潜力。
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