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Development of an efficient NUPR1 inhibitor with anticancer activity.

Xi Liu1, Ana Jimenez-Alesanco2, Zexian Li3

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Summary

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.

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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.