Anticancer Drug Conjugates Incorporating Estrogen Receptor Ligands

Abstract

Hormone-dependent cancers, such as certain types of breast cancer are characterized by over-expression of estrogen receptors (ERs). Anticancer drug conjugates combining ER ligands with other classes of anticancer agents may not only benefit from dual action at both anti-cancer targets but also from selective delivery of cytotoxic agents to ER-positive tumor cells resulting in less toxicity and adverse effects. Moreover, they could also take advantage of overcoming resistance typical for anti-hormonal monotherapy such as tamoxifen. In this review, we discuss the design, structures and pharmacological effects of numerous series of drug conjugates containing ER ligands such as selective ER modulators (tamoxifen, 4-hydroxytamoxifen, endoxifen), selective ER degraders (ICI-164384) and ER agonists (estradiol) linked to diverse anti-cancer agents including histone-deacetylase inhibitors, DNA-alkylating agents, antimitotic agents and epidermal growth factor receptor inhibitors.

PROTACs: A novel strategy for cancer drug discovery and development

“…However, drug resistance caused by long‐term clinical use limited their therapeutic efficacy. Furthermore, the oral bioavailability of existing breast cancer drugs, such as selective ER degrader fulvestrant, can only be administered by intramuscular injection 209,210 . The emergence of PROTACs provides a new approach for the discovery and development of ERα targeted drugs.…”