Design, synthesis and biological evaluation of novel dual-acting modulators targeting both estrogen receptor alpha (ER alpha) and lysine-specific demethylase 1 (LSD1) for treatment of breast cancer

摘要

Breast cancer is a multi-factor disease, thus more and more drug combination therapies are applied in the treatment. However, there are undeniable disadvantages in drug combination therapy. Therefore, the development of new dual-targeting drugs has become a new strategy. In this study, we have developed a series of dual-acting agents targeting both estrogen receptor alpha (ER alpha) and histone demethylase based on a privileged OBHS pharmacophore scaffold developed previously by our laboratory. These novel OBHS-LSD1i conjugates showed excellent ER alpha binding affinity and selectivity, and exhibited potent inhibitory activity against lysine specific demethylase 1 (LSD1). Several conjugates showed higher anti-proliferative efficacy in MCF-7 breast cancer cell line compared to 4-hydroxytamoxifen in vitro. Among them, the best compound mu g displayed potent inhibitory activity against LSD1 and MCF-7 cells with IC50 values of 1.55 mu M and 8.79 mu M, respectively. Flow cytometry analysis of apoptosis of mu g suggested that the effect of this type compounds on MCF-7 cells is partly caused by inducing apoptosis. Moreover, the molecular docking of mu g with ER alpha and the active site of LSD1/CoREST complex provides practical way for understanding the dual mechanism actions of this kind of compounds with the targets. As such, these compounds have shown potential to become promising leads for the development of highly efficient dual-acting modulators for breast cancer therapies. (C) 2020 Elsevier Masson SAS. All rights reserved.