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The MDM4 Inhibitor CEP-1347 Activates Wild-type p53 in Ovarian Clear Cell Carcinoma Cells and Potently Inhibits their

Yasufumi Ito1,2, Kazuki Nakamura1,3, Yurika Nakagawa-Saito1

  • 1Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.

Anticancer Research
|October 28, 2025
PubMed
Abstract

Insights

CEP-1347, an MDM4 inhibitor, reactivates the p53 pathway and inhibits ovarian clear cell carcinoma (OCCC) growth. This study suggests targeting MDM4 is a promising therapeutic strategy for OCCC with wild-type p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Ovarian clear cell carcinoma (OCCC) rarely harbors TP53 mutations, unlike high-grade serous carcinoma.
  • Reactivating the p53 pathway presents a therapeutic opportunity for OCCC.
  • MDM4, a negative regulator of p53, is a potential therapeutic target.

Purpose of the Study:

  • Investigate the impact of CEP-1347, an MDM4 inhibitor, on p53 pathway activity.
  • Evaluate the effect of CEP-1347 on OCCC cell growth.
  • Assess the therapeutic potential of targeting MDM4 in OCCC.

Main Methods:

  • Utilized RT-PCR and western blot to analyze p53 pathway components.
  • Employed dye exclusion and colony formation assays to assess cell growth.
  • Examined CEP-1347 effects in OCCC cell lines with and without p53 mutations.

Main Results:

  • CEP-1347 decreased MDM4 and increased p53 and p21 expression in a p53-dependent manner.
  • MDM4 knockdown mimicked CEP-1347 effects, increasing p53 and p21.
  • CEP-1347 inhibited OCCC cell growth and survival without toxicity to normal cells.

Conclusions:

  • Targeting MDM4 with CEP-1347 shows therapeutic potential for OCCC.
  • CEP-1347 effectively reactivates the p53 pathway in OCCC.
  • This strategy is particularly relevant for OCCC with wild-type p53.
Keywords:
CEP-1347HDMXMDMXclear cell ovarian cancerdrug repositioning

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