A novel PAAoptosis-inducing ERRα-targeting compound for combating hematopoietic and solid cancers

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Estrogen-related receptor-alpha (ERRα) is implicated in driving cancer progression.
• Developing targeted therapeutics for ERRα is a key area in cancer research.

Purpose of the Study:

• To design and evaluate a novel compound, PAMT-001, as an ERRα-targeting therapeutic.
• To investigate the anticancer mechanisms and potential of PAMT-001.

Main Methods:

• Protein-small molecule binding assays and luciferase assays were used to confirm ERRα interaction.
• Anticancer effects were assessed in hematological and solid tumor models.
• Mechanistic studies involved evaluating mitochondrial function, reactive oxygen species production, endoplasmic reticulum stress, autophagy, and pyroptosis.

Main Results:

• PAMT-001 demonstrated significant interaction with ERRα and suppressed tumorigenesis.
• Despite lower potency than XCT-790, PAMT-001 exhibited stronger anticancer effects across tumor types.
• PAMT-001 induced apoptosis, excessive autophagy, and gasdermin E-mediated pyroptosis, termed 'PAAoptosis'.

Conclusions:

• PAMT-001 is a potent ERRα-targeting anticancer agent.
• The compound induces cancer cell death through a novel combination of apoptosis, autophagy, and pyroptosis.
• PAMT-001 shows potential for precision medicine, especially in chemotherapy-resistant acute myeloid leukemia.