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Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity

Yi Yuan1, Dingqiang Fu1, Yan Xu1

  • 1Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.

Journal of Medicinal Chemistry
|November 16, 2022
PubMed

Insights

A new platinum(IV) prodrug, AP1, effectively targets the base excision repair (BER) pathway protein APE1. AP1 shows superior efficacy against resistant cancers and inhibits tumor growth with minimal toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The base excision repair (BER) pathway is crucial for cancer cells to develop resistance to chemotherapy.
  • Targeting BER offers a potential strategy to overcome treatment resistance.
  • Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in the BER pathway.

Purpose of the Study:

  • To develop and evaluate a novel platinum(IV) prodrug, AP1, designed to target APE1.
  • To investigate the mechanism of action and efficacy of AP1 in cancer treatment.
  • To assess the potential of AP1 in overcoming cisplatin resistance.

Main Methods:

  • Synthesis and characterization of the Pt(IV) prodrug AP1.
  • In vitro studies assessing AP1's cytotoxicity against various cancer cell lines, including cisplatin-resistant ones.
  • In vivo efficacy studies using a xenograft cancer model.
  • Investigation of AP1's effect on DNA damage response, apoptosis, and APE1 activity.

Main Results:

  • AP1 demonstrated significant inhibition of cancer cell growth, outperforming cisplatin, especially in resistant cell lines (up to 18.11-fold inhibition).
  • AP1 showed comparable toxicity to normal cells as cisplatin.
  • In vivo studies revealed AP1 to be 3.86-fold more potent than cisplatin without adverse effects.
  • AP1 directly inhibited APE1 endonuclease activity, leading to miRNA processing disruption and PTEN upregulation.

Conclusions:

  • AP1 is a promising novel Pt(IV) prodrug targeting APE1 and the BER pathway.
  • AP1 effectively inhibits cancer cell growth, including cisplatin-resistant types, with a favorable safety profile.
  • The findings highlight the therapeutic potential of targeting BER via APE1 inhibition for enhanced cancer treatment.

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