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

Author:

Chen Ceshi1ORCID,Kong Yanjie2,Lan Tianlong,Wang Luzhen,Huang Haihui,Lv Wenxing,Zhou Chengang,Sun Xiuyun,Weng Xin,Cai Chang,Peng Wenfeng,Zhang Meng,Jiang Dewei3ORCID,Yang Chuanyu2,Liu Xia,Rao Yu4ORCID

Affiliation:

1. Kunming Medical University

2. Kunming Institute of Zoology

3. Kunming Institute of Zoology, CAS

4. Tsinghua University

Abstract

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 biodegradabilityand 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.

Publisher

Springer Science and Business Media LLC

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