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Abstract <p><b>Objective:</b> Many studies have reported that EZH2 is a promising anti-tumor target. <b>Methods:</b> The target compounds were synthesized through multi-step reactions involving amide coupling and palladium-catalyzed cross-coupling, with structures confirmed by HR-ESI-MS and <sup>1</sup>H, <sup>13</sup>C NMR spectroscopy. Biological evaluations included <i>in vitro</i> cell viability assays (CCK-8), EZH2 enzyme inhibition assays, molecular docking studies, and ADMET property predictions to assess pharmacokinetic profiles. <b>Results and Discussion:</b> In this study, four small-molecule inhibitors targeting EZH2 were designed and synthesized, using loureirin C as the lead compound. The results of the CCK-8 assay showed that compound (<b>DD1</b>) had a stronger inhibitory effect on the viability of A375 cells. In addition, compound (<b>DD1</b>) exhibited an <i>in vitro</i> enzyme inhibitory effect comparable to that of tazemetostat. Molecular docking studies demonstrated that compound (<b>DD1</b>) could enter the active site and interact with key amino acid residues. Pharmacokinetic prediction indicated that compound (<b>DD1</b>) had favorable biological activity, with relative index values comparable to those of positive control drugs. <b>Conclusions:</b> In summary, we have successfully synthesized a series of EZH2 inhibitors that are expected to represent an attractive therapeutic strategy for tumors.</p>

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Design, Synthesis, and Biological Evaluation of Novel EZH2 Inhibitors

  • 期刊论文

  • 发表日期：

    2025年7月28日

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  • Dan Wang,
  • Ming-Tao Xia,
  • Xiang Li,
  • Ru-Xing Wang,
  • Ling Yu,
  • Shuai Li

摘要

Abstract

Objective: Many studies have reported that EZH2 is a promising anti-tumor target. Methods: The target compounds were synthesized through multi-step reactions involving amide coupling and palladium-catalyzed cross-coupling, with structures confirmed by HR-ESI-MS and 1H, 13C NMR spectroscopy. Biological evaluations included in vitro cell viability assays (CCK-8), EZH2 enzyme inhibition assays, molecular docking studies, and ADMET property predictions to assess pharmacokinetic profiles. Results and Discussion: In this study, four small-molecule inhibitors targeting EZH2 were designed and synthesized, using loureirin C as the lead compound. The results of the CCK-8 assay showed that compound (DD1) had a stronger inhibitory effect on the viability of A375 cells. In addition, compound (DD1) exhibited an in vitro enzyme inhibitory effect comparable to that of tazemetostat. Molecular docking studies demonstrated that compound (DD1) could enter the active site and interact with key amino acid residues. Pharmacokinetic prediction indicated that compound (DD1) had favorable biological activity, with relative index values comparable to those of positive control drugs. Conclusions: In summary, we have successfully synthesized a series of EZH2 inhibitors that are expected to represent an attractive therapeutic strategy for tumors.