Data from Identification of an imidazopyridine-based compound as an oral selective estrogen receptor degrader for breast cancer therapy
Year: 2023
Type: other
Abstract: The pro-oncogenic activities of estrogen receptor alpha (ER) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ER are therefore used to prevent primary disease metastasis. Although recent successes with ER degraders have been reported, there is still the need to develop further ER antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor positive (AR+) prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of ER+ breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ER and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers.
Authors: Mengwu Pan, Valeria Solozobova, Nane C. Kuznik, Nicole Jung, Simone Graessle, Victor Gourain, Yvonne M. Heneka, Christina Alexandra Cramer von Clausbruch, Olaf Fuhr, Ravi S.N. Munuganti, Danilo Maddalo, Christine Blattner, Antje Neeb, Adam Sharp, Laura Cato, Carsten Weiss, Rinath M. Jeselsohn, Veronique Orian-Rousseau, Stefan Bräse, Andrew C.B. Cato
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4383555434