Identification of an imidazopyridine-based compound as an oral selective estrogen receptor degrader for breast cancer therapy

Abstract The pro-oncogenic activities of estrogen receptor alpha (ER) drive breast cancer pathogenesis. Endocrine therapies that impair the production or action ER are therefore used to prevent primary disease metastasis. Although recent successes with degraders have been reported, there is still need develop further antagonists additional properties for therapy. We previously described a benzothiazole compound A4B17 inhibits proliferation androgen positive (AR+) prostate cells by disrupting interaction cochaperone BAG1 AR. was also found inhibit ER+ cells. Using scaffold hopping approach, we report here group small molecules imidazopyridine scaffolds more potent and efficacious than A4B17. prototype molecule X15695 efficiently degraded attenuated estrogen-mediated target gene expression as well transactivation disrupted key cellular protein-protein interactions such BAG1-mortalin (GRP75) wild-type p53-mortalin mutant p53-BAG2 interactions. These together reactivated p53 resulted in cell cycle block induction apoptosis. When administered orally vivo tumor xenograft models, potently inhibited growth but less identify an oral selective ER degrader propose development this therapy cancers.