2. Academic Validation
  3. Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both In Vitro and In Vivo

Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both In Vitro and In Vivo

  • J Med Chem. 2024 Apr 25;67(8):6658-6672. doi: 10.1021/acs.jmedchem.4c00141.
Qi-Xuan Huang 1 2 3,  Da-Meng Fan 1 2 3,  Zao-Zao Zheng 1 2 3,  Ting Ran 4,  Ao Bai 1 2 3,  Rong-Quan Xiao 1 2 3,  Guo-Sheng Hu 1 2 3,  Wen Liu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
  • 3 Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
  • 4 Bioland Laboratory (Guangzhou Regenerative Medicine and Health─Guangdong Laboratory), KaiYuan Road, Guangzhou, Guangdong 510530, China.
PMID: 38569135 DOI: 10.1021/acs.jmedchem.4c00141
Abstract

BRD4 is associated with a variety of human diseases, including breast Cancer. The crucial roles of amino-terminal bromodomains (BDs) of BRD4 in binding with acetylated histones to regulate oncogene expression make them promising drug targets. However, adverse events impede the development of the BD inhibitors. BRD4 adopts an extraterminal (ET) domain, which recruits proteins to drive oncogene expression. We discovered a peptide inhibitor PiET targeting the ET domain to disrupt BRD4/JMJD6 interaction, a protein complex critical in oncogene expression and breast Cancer. The cell-permeable form of PiET, TAT-PiET, and PROTAC-modified TAT-PiET, TAT-PiET-PROTAC, potently inhibits the expression of BRD4/JMJD6 target genes and breast Cancer cell growth. Combination therapy with TAT-PiET/TAT-PiET-PROTAC and JQ1, iJMJD6, or Fulvestrant exhibits synergistic effects. TAT-PiET or TAT-PiET-PROTAC treatment overcomes endocrine therapy resistance in ERα-positive breast Cancer cells. Taken together, we demonstrated that targeting the ET domain is effective in suppressing breast Cancer, providing a therapeutic avenue in the clinic.

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