Development of an efficient NUPR1 inhibitor with anticancer activity

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.