Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor-targeting PROTACs

摘要

Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, eventually hormone-sensitive ER-positive cancer cells develop resistance to ER antagonists. It has been shown that, in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies propose that tamoxifen initially acts as an antagonist but later functions as an ER agonist, promoting tumor growth. This suggests that targeted ER degradation may provide an effective therapeutic approach for breast cancers, even those which are resistant to conventional therapies. With this in mind, we previously demonstrated that PROTACs effectively induce degradation of the ER as a proof of concept experiment. Herein, we further refined the PROTAC approach to target the ER for degradation. The ER-targeting PROTACs are composed of an estradiol on one end and Hypoxia Inducing Factor 1α (HIF-1α)-derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the ER to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on estradiol to generate three different types of PROTACs. When the pentapeptide is linked through the C-7α position of estradiol, the resulting PROTAC showed the most effective ER degradation and best affinity for the estrogen receptor. This result provides an opportunity to develop a novel type of ER antagonist that may overcome the resistance of breast tumor to conventional drugs, such as tamoxifen and fulvestrant (Faslodex^™).