Design and synthesis of novel benzothiophene analogs as selective estrogen receptor covalent antagonists against breast cancer

Endocrine therapy (ET) has benefited patients with estrogen receptor alpha (ER alpha) positive breast cancer for decades. Selective estrogen receptor modulator (SERM) such as Tamoxifen represents the clinical standard of care (SoC). Despite the therapeutic importance of current SoC agents, 30-50% of prolonged treatment patients inevitably generated resistant tumor cells, usually eventually suffered tumor relapse and developed into metastatic breast cancer (MBC), which was the leading cause of female cancer-related mortality. Among these, most resistant tumors remained dependent on ER alpha signaling, which reignited the need for the next generation of ER alpha related agents. We hypothesized that selective estrogen receptor covalent antagonists targeting ER alpha would provide a therapeutic alternative. In the current work, series of novel benzothiophene hybrids bearing electrophile moieties were synthesized and biologically evaluated. The representative analogue 15c exhibited potent anti-proliferative effect in MCF-7 cell lines in vitro, and further mechanism studies confirmed the necessity of covalent bonding. More importantly, 15c could attenuate the expression of TFF-1, GREB-1 and downregulate the levels of cellular ER alpha protein. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Endocrine therapy has been beneficial for breast cancer patients with ER alpha positive tumors for decades, but the development of resistance remains a challenge. The exploration of new ER alpha targeted agents is crucial to overcome therapy resistance and improve patient outcomes.