Discovery of a novel lead compound targeting BRD4 BD2 with a di-phenyl ether fragment: Synthesis, molecular docking and drug-likeness studies

Abstract

A series of di-phenyl ether derivatives were designed and synthesized through structure-based virtual screening followed by chemical optimization. 17 new compounds were submitted to activity evaluation against BRD4 BD2 utilizing the time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Compound 10 exhibited good inhibitory activity to BRD4 BD2 with an IC₅₀ value of 0.95 μM. The molecular docking studies revealed the binding mechanism of the inhibitors to BRD4 BD2. Drug-likeness predictions demonstrated acceptable drug-like profiles of representative compounds. The resulting compound 10 represents a new lead compound for further optimization to generate more potent inhibitors of BRD4 BD2.

Graphical abstract

A hit compound with weak binding activity was identified through virtual screening of an in-house library comprising 1,000 compounds, followed by TR-FRET assay validation of representative candidates. Structural optimization of this hit led to the discovery of a potent BRD4 BD2 inhibitor featuring a novel di-phenyl ether-coupled benzisoxazole scaffold.