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

Shuxia Chen; Jichen Yang; Xiangyu Wang; Xiaochun Liu; Xiuxue Li; Yansheng Ye; Pingyuan Wang; Zhiqing Liu; Chang-Yun Wang

doi:10.1016/j.ejmech.2024.117193

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

Eur J Med Chem. 2024 Dec 24:284:117193. doi: 10.1016/j.ejmech.2024.117193. Online ahead of print.

Authors

Shuxia Chen¹, Jichen Yang¹, Xiangyu Wang¹, Xiaochun Liu², Xiuxue Li³, Yansheng Ye⁴, Pingyuan Wang⁵, Zhiqing Liu⁶, Chang-Yun Wang⁷

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: [email protected].
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: [email protected].
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: [email protected].

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.