Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer

Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent prooncogenic signaling, by targeting Estrogen Receptor (ER) alpha with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ER alpha represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ER alpha in the sub-mu M range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERa levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Breast cancer is a major cause of death in women globally, and the development of dual acting molecules targeting aromatase and estrogen receptor alpha may provide a promising alternative strategy to combat estrogen receptor positive breast cancer. This study identifies key structural features needed for optimal dual acting drug candidates, demonstrating the potential of multitarget compounds as a viable therapeutic option for ER+ BC.