Scholarlink

<p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The epigenetic regulator EZH2 is a promising therapeutic target due to its role in tumor progression and therapy resistance. This study combined computational and experimental methods to repurpose FDA-approved drugs as EZH2 inhibitors. Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (−10.90&#xa0;kcal/mol) and complex stability compared to the known inhibitor GSK126. ADT formed robust hydrogen bonds and hydrophobic interactions with key residues in the EZH2 binding site, supported by favorable binding free energy calculations (ΔGbinding = −34.73&#xa0;kcal/mol). In vitro, ADT exhibited selective cytotoxicity against NSCLC A549 cells (IC₅₀ = 32.4&#xa0;nM) versus normal bronchial epithelial cells (IC₅₀ = 190&#xa0;nM). Treatment with ADT significantly reduced EZH2 expression and potently inhibited its histone methyltransferase activity, as directly evidenced by decreased global H3K27me3 levels. ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.</p> Graphical abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Repurposing acetyldigitoxin as a potential EZH2 inhibitor for non-small cell lung cancer: a computational and experimental approach

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月6日

查看全文
  • Xiang Ji,
  • Xiyan Wang,
  • Ting Xiu,
  • Min Gao,
  • Degan Lu

摘要

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The epigenetic regulator EZH2 is a promising therapeutic target due to its role in tumor progression and therapy resistance. This study combined computational and experimental methods to repurpose FDA-approved drugs as EZH2 inhibitors. Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (−10.90 kcal/mol) and complex stability compared to the known inhibitor GSK126. ADT formed robust hydrogen bonds and hydrophobic interactions with key residues in the EZH2 binding site, supported by favorable binding free energy calculations (ΔGbinding = −34.73 kcal/mol). In vitro, ADT exhibited selective cytotoxicity against NSCLC A549 cells (IC₅₀ = 32.4 nM) versus normal bronchial epithelial cells (IC₅₀ = 190 nM). Treatment with ADT significantly reduced EZH2 expression and potently inhibited its histone methyltransferase activity, as directly evidenced by decreased global H3K27me3 levels. ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.

Graphical abstract