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Development of an efficient NUPR1 inhibitor with anticancer activity

Xi Liu1, Ana Jimenez-Alesanco2, Zexian Li3

  • 1Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France.

Scientific Reports
|November 28, 2024
PubMed

Insights

A new drug candidate, AJO14, effectively targets nuclear protein 1 (NUPR1) in pancreatic cancer cells, inducing cell death without cardiotoxicity. Derivatives show enhanced efficacy, offering a safer treatment option.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Pancreatic cancer is a lethal disease with limited therapeutic options.
  • Previous drug candidate ZZW-115 targeted nuclear protein 1 (NUPR1) but showed cardiotoxicity due to hERG channel interaction.
  • Need for safer, effective NUPR1 inhibitors for pancreatic cancer treatment.

Purpose of the Study:

  • To identify a novel NUPR1 inhibitor with reduced cardiotoxicity.
  • To evaluate the anti-cancer efficacy of the identified compound and its derivatives.
  • To investigate the mechanism of action of the novel compound.

Main Methods:

  • High-throughput screening of 10,000 compounds to identify NUPR1 binders without hERG affinity.
  • In vitro assessment of AJO14's mechanism of cell death induction (apoptosis, necroptosis, parthanatos) and mitochondrial function.
  • In vivo efficacy studies in xenografted mice and molecular modification of AJO14 to generate derivatives.

Main Results:

  • AJO14 identified as a lead compound targeting NUPR1 without hERG affinity.
  • AJO14 induced pancreatic cancer cell death via apoptosis, necroptosis, and parthanatos, linked to mitochondrial dysfunction and hyperPARylation.
  • AJO14 demonstrated dose-dependent tumor reduction in vivo; 8 derivatives showed enhanced efficacy, including LZX-2-73.

Conclusions:

  • AJO14 is a promising NUPR1 inhibitor for pancreatic cancer with a favorable safety profile regarding cardiotoxicity.
  • AJO14-derived compounds exhibit potent anti-cancer activity and warrant further investigation for clinical development.
  • These novel compounds offer a potential new therapeutic strategy for pancreatic cancer.

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