2. Academic Validation
  3. Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity

Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity

  • Eur J Med Chem. 2025 Feb 15:284:117193. doi: 10.1016/j.ejmech.2024.117193.
Shuxia Chen 1,  Jichen Yang 1,  Xiangyu Wang 1,  Xiaochun Liu 2,  Xiuxue Li 3,  Yansheng Ye 4,  Pingyuan Wang 5,  Zhiqing Liu 6,  Chang-Yun Wang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
  • 2 Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao, 266003, China.
  • 3 Qingdao Academy of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Qingdao, 266114, China.
  • 4 Key Laboratory of Magnetic Resonance in Biological System, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 5 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. Electronic address: wangpingyuan@ouc.edu.cn.
  • 6 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. Electronic address: liuzhiqing@ouc.edu.cn.
  • 7 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. Electronic address: changyun@ouc.edu.cn.
PMID: 39740323 DOI: 10.1016/j.ejmech.2024.117193
Abstract

Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3H)-ones with diverse linkers between two aromatic ring systems. Among them, compound 25 possessed good in vitro BRD4 inhibitory activities (IC50 = 3.64 μM for BRD4 BD1 and IC50 = 0.12 μM for BRD4 BD2) and anti-inflammatory activity (IC50 = 1.98 μM for NO production assay). Meantime, 25 obviously suppressed the expression of TNF-α and IL-6 in LPS-stimulated Raw 264.7 and THP-1 cells. Notablely, 25 displayed in vivo therapeutic efficacies in an acute inflammation model without obvious cytotoxicity. These findings suggest that 25 is a selective BRD4 BD2 Inhibitor which is a promising anti-inflammatory lead compound worthy for further investigation.

Keywords

Anti-inflammatory activity; Quinazolin-4(3H)-one; SAR; Selective BRD4 BD2 inhibitor.

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