Inhibition of breast cancer growth with AN-329, a novel Hsp110 inhibitor, by inactivating p-STAT3/c-Myc axis

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by its propensity for metastasis. Heat shock protein 110 (Hsp110), a molecular chaperone encoded by the HSPH1 gene, has been implicated in cancer progression, including breast cancer, where it is upregulated and associated with worse outcomes. However, the role of Hsp110 in breast cancer pathogenesis and its potential as a therapeutic target have not been thoroughly investigated. This study utilized the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database to analyze HSPH1 gene expression in breast cancer and its correlation with tumor progression and survival. Furthermore, a comprehensive screen of the Specs database led to the identification of AN-329, a novel inhibitor that binds directly to the nucleotide-binding domain of Hsp110, neutralizing its chaperone activity and inhibiting breast cancer cell growth. AN-329 was validated in vitro for its antitumor efficacy and was found to regulate the cell cycle through the p-STAT3/c-Myc axis. This work suggests that AN-329 could be a promising lead for developing innovative therapeutic agents against breast cancer, warranting further research and potential clinical translation. •Hsp110 is overexpressed in breast cancer tissues and high Hsp110 expression is associated with poorer prognosis.•The novel Hsp110 inhibitor, identified as AN-329, effectively blocks the biochemical and chaperone functions of Hsp110.•AN-329 exhibits potent inhibitory effects on breast cancer cell proliferation with minimal effects on normal breast cells.•The study reveals that AN-329 induces cell cycle arrest at the G1 phase through the p-STAT3/c-Myc axis.•The study suggests that targeting Hsp110 could be a promising strategy for personalized treatment of breast cancer.