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

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.