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

Estrogen-related receptor-α (ERRα; NR3B1) is an orphan nuclear receptor that drives the progression of several cancers. To develop novel ERRα-targeting therapeutics, we designed and evaluated the function of a new compound, PAMT-001, which interacts with ERRα and effectively suppresses tumorigenesis. We demonstrated a significant interaction between ERRα and PAMT-001 using protein-small molecule binding assays and luciferase assays. Although PAMT-001 exhibited lower activity compared to the established ERRα inverse agonist XCT-790, it showed stronger anticancer effects against both hematological and solid tumors. Mechanistically, PAMT-001 promoted combined cell death mechanisms in tumors. It disrupted mitochondrial respiratory function and structure, leading to excessive production of reactive oxygen species and endoplasmic reticulum stress, ultimately resulting in apoptotic cell death. Additionally, PAMT-001 induced excessive autophagy, contributing to cancer cell death, as well as gasdermin E-mediated pyroptosis in acute myeloid leukemia and colon cancer cells. Furthermore, PAMT-001 demonstrated potential for use in precision medicine, particularly for patients with chemotherapy-resistant and NPM1-mutated acute myeloid leukemia. PAMT-001 is a potent ERRα-targeting anticancer agent capable of inducing anticancer effects through pyroptosis, autophagic cell death, and apoptosis-a newly termed mechanism referred to as "PAAoptosis." It holds significant potential for the treatment of both hematological and solid cancers.