2. Academic Validation
  3. BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression

BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression

  • Oncogene. 2024 Sep;43(39):2914-2926. doi: 10.1038/s41388-024-03121-1.
Yanjie Kong 1,  Tianlong Lan 2,  Luzhen Wang 3,  Chen Gong 4,  Wenxin Lv 2,  Hailin Zhang 3,  Chengang Zhou 3,  Xiuyun Sun 2,  Wenjing Liu 5,  Haihui Huang 1,  Xin Weng 1,  Chang Cai 1,  Wenfeng Peng 1,  Meng Zhang 1,  Dewei Jiang 3,  Chuanyu Yang 3,  Xia Liu 6,  Yu Rao 7,  Ceshi Chen 8 9 10
Affiliations

Affiliations

  • 1 Pathology Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
  • 2 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4 Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 5 The Third Affiliated Hospital, Kunming Medical University, Kunming, China.
  • 6 Pathology Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China. mdcg2014bl@163.com.
  • 7 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China. yrao@tsinghua.edu.cn.
  • 8 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • 9 The Third Affiliated Hospital, Kunming Medical University, Kunming, China. chenc@mail.kiz.ac.cn.
  • 10 Academy of Biomedical Engineering, Kunming Medical University, Kunming, China. chenc@mail.kiz.ac.cn.
PMID: 39164524 DOI: 10.1038/s41388-024-03121-1
Abstract

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.

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