2. Academic Validation
  3. Discovery of a potent BRD4 PROTAC and evaluation of its bioactivity in breast cancer cell lines

Discovery of a potent BRD4 PROTAC and evaluation of its bioactivity in breast cancer cell lines

  • Biochem Pharmacol. 2025 Jul 12:241:117159. doi: 10.1016/j.bcp.2025.117159.
Junjie Hu 1,  Jincui Yang 2,  Runxuan Zhou 3,  Ke Chen 4,  Hongyun Zhao 5,  Yirong Zhou 6
Affiliations

Affiliations

  • 1 Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat- Sen University Cancer Center, Guangzhou, China.
  • 2 Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3 Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jie Fang Avenue, Wuhan, China.
  • 4 Department of Urology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jie Fang Avenue, Wuhan, China. Electronic address: Kechen@hust.edu.cn.
  • 5 Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat- Sen University Cancer Center, Guangzhou, China. Electronic address: zhaohy@sysucc.org.cn.
  • 6 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhouyirong@hust.edu.cn.
PMID: 40659131 DOI: 10.1016/j.bcp.2025.117159
Abstract

Proteolysis targeting chimeras (PROTACs) targeting bromodomain-containing protein 4 (BRD4) proved to be powerful BRD4 degraders, which showed superiority in vitro and in vivo anti-tumor activity in many Cancer models. Referring to the design of ARV-825, ARV-771 and MZ1, two novel BRD4 PROTACs were rationally designed and prepared via connecting the pan-BET selective bromodomain inhibitor JQ1 and two universal E3 Ligase ligands targeting Von Hippel-Lindau (VHL) and Cereblon (CRBN), namely VHL-JQ1 and CRBN-JQ1. Comparable to the degradation potency of ARV-825, ARV-771, and MZ1, both BRD4 PROTACs demonstrated potent BRD4 degradation efficacy. VHL-JQ1 showed superior antitumor activity against triple-negative breast Cancer (TNBC) cell lines across multiple cellular processes, including cell proliferation suppression, migration and invasion inhibition, cell cycle arrest, and Apoptosis induction. In addition, RNA-seq analysis revealed both shared and distinct gene expression profiles between BRD4 PROTAC-treated and JQ1-treated cells. Notably, VHL-JQ1 induced more pronounced mRNA expression changes compared to CRBN-JQ1 and JQ1. KRAS and Notch signaling pathways might be involved in the transcriptomic differences induced by BRD4 PROTACs and JQ1 treatment. Furthermore, combination therapy studies revealed that VHL-Q1 exhibited antagonistic effects when combined with paclitaxel, while demonstrating synergistic effects with cisplatin in TNBC treatment. Overall, our findings highlight VHL-JQ1 as a promising chemical probe for investigating BRD4 biological functions and a potential therapeutic candidate for TNBC treatment.

Keywords

BRD4; JQ1; PROTAC; Triple-negative breast cancer.

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