BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression
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.
Authors
- Xin Weng (ORCID: https://orcid.org/0000-0002-3828-6783)
- Tianlong Lan (ORCID: https://orcid.org/0000-0002-9435-9959)
- Huang Haihui (ORCID: https://orcid.org/0000-0003-3803-5877)
- Ceshi Chen (ORCID: https://orcid.org/0000-0001-6398-3516)
- Chengang Zhou
- Meng Zhang (ORCID: https://orcid.org/0000-0003-1941-1136)
- Dewei Jiang (ORCID: https://orcid.org/0000-0002-7773-5449)
- Xia Liu (ORCID: https://orcid.org/0000-0002-0180-2166)
- Wenjing Liu (ORCID: https://orcid.org/0000-0001-5081-9047)
- Gong Chen (ORCID: https://orcid.org/0000-0002-5067-9889)
- Chang Cai
- Wenfeng Peng
- Xiuyun Sun
- Hailin Zhang (ORCID: https://orcid.org/0000-0002-7663-0418)
- Wenxin Lv
- Yu Rao (ORCID: https://orcid.org/0000-0002-4356-8531)
- Chuanyu Yang
- Yanjie Kong
- Luzhen Wang
Institutions
- Kunming Institute of Zoology (CN)
- Chinese Academy of Sciences (CN)
- Kunming Medical University (CN)
- Shenzhen Second People's Hospital (CN)
- University of Hong Kong (HK)
- Tsinghua University (CN)
Publication Details
- Journal
- Oncogene
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1038/s41388-024-03121-1
- Citations
- 14
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province