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<p>PROTAC is a drug development technology that uses the Ubiquitin-Proteasome System (UPS) to degrade target proteins, and enhances the degradation ability of target proteins through E3 ubiquitin ligase, which can further enhance the anti-tumor effect of targeted drug molecules. In this study, a series of dual-target MDM2/MDMX stapled peptide PROTAC based on SM3-4 were designed and synthesized, and the stapled peptide PROTAC DSM3-2 and DSM3-5 screened in the study inhibited tumor cell growth in vitro at low µM concentrations. The results showed that the enhancement of stapled peptide activity was positively correlated with the increase of helicity, which provided an effective research basis for the dual-target anti-tumor stapled peptide PROTAC. Molecular docking experiments have shown that the binding peptide DSM3-2 can effectively bind to the target proteins MDM2 and MDMX to exert a dual targeting effect on tumor cells.</p>

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Study on the design, synthesis and activity of MDM2/MDMX anti-tumor stapled peptide PROTAC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Xiufei Liao,
  • Mao Guo,
  • Damin Hu,
  • Chunli Su,
  • Hongli Liao

摘要

PROTAC is a drug development technology that uses the Ubiquitin-Proteasome System (UPS) to degrade target proteins, and enhances the degradation ability of target proteins through E3 ubiquitin ligase, which can further enhance the anti-tumor effect of targeted drug molecules. In this study, a series of dual-target MDM2/MDMX stapled peptide PROTAC based on SM3-4 were designed and synthesized, and the stapled peptide PROTAC DSM3-2 and DSM3-5 screened in the study inhibited tumor cell growth in vitro at low µM concentrations. The results showed that the enhancement of stapled peptide activity was positively correlated with the increase of helicity, which provided an effective research basis for the dual-target anti-tumor stapled peptide PROTAC. Molecular docking experiments have shown that the binding peptide DSM3-2 can effectively bind to the target proteins MDM2 and MDMX to exert a dual targeting effect on tumor cells.