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FIGURE 8 from Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy

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posted on 2023-07-27, 14:20 authored by Mengwu Pan, Valeria Solozobova, Nane C. Kuznik, Nicole Jung, Simone Gräßle, Victor Gourain, Yvonne M. Heneka, Christina A. 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

X15695 induces cell-cycle arrest and inhibits proliferation of AR+ and ER+ prostate and breast cancer cells. Cell-cycle profile measured by flow cytometry of LNCaP (A) and LAPC-4 cells (B) treated with vehicle or 1 μmol/L X15695 for 48 hours. Cells for flow cytometry were stained with DRAQ5. The quantified results are the mean ± SEM (n = 3; *, P ≤ 0.05; **, P ≤ 0.01). C, Representative examples of LAPC-4 xenograft mouse tumors after daily treatment with vehicle, X15695 (10 and 30 mg/kg), and enzalutamide (10 mg/kg) for 43 days. D, Tumor weights at the end of treatment were recorded and presented as a bar chart. The values are the means ± SEM expressed (**, P ≤ 0.01; ****, P ≤ 0.0001; n = 14; ns, not significant). E, Mouse body weights were measured twice weekly over the 43 days. Presented are the mouse body weight changes, in percentages, for each group. F, Quantification of the effect of the indicated concentrations of X15695 on clonal expansion of the indicated tumor cells (n = 3).

Funding

Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)

China Scholarship Council (CSC)

Prostate Cancer UK (Prostate Cancer)

History

ARTICLE ABSTRACT

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.