Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

Autor:	Pan M; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Solozobova V; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Kuznik NC; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Jung N; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Gräßle S; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Gourain V; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France., Heneka YM; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Cramer von Clausbruch CA; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Fuhr O; Institute of Nanotechnology and Karlsruhe Nano Micro Facility (KNMFi), Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Munuganti RSN; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Maddalo D; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Blattner C; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Neeb A; Institute of Cancer Research, London, United Kingdom., Sharp A; Institute of Cancer Research, London, United Kingdom.; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom., Cato L; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Weiss C; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Jeselsohn RM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Orian-Rousseau V; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany., Bräse S; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.; Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany., Cato ACB; Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Jul 27; Vol. 3 (7), pp. 1378-1396. Date of Electronic Publication: 2023 Jul 27 (Print Publication: 2023).
DOI:	10.1158/2767-9764.CRC-23-0111
Abstrakt:	The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (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 ERα 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. Significance: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER + breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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