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<p>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 <b>10</b> exhibited good inhibitory activity to BRD4 BD2 with an IC<sub>50</sub> value of 0.95 <i>μ</i>M. 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 <b>10</b> represents a new lead compound for further optimization to generate more potent inhibitors of BRD4 BD2.</p> Graphical abstract <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月2日

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  • Maofeng Zhang,
  • Liguang Zhang,
  • Yan Zhang,
  • Xin Feng,
  • Rui Liang,
  • Songbai Liu

摘要

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.