Estrogen receptor-alpha (ER) antagonists have been widely used for
breast cancer therapy. Despite initial responsiveness,
hormone-sensitive ER-positive
cancer cells eventually 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 indicate 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 that are resistant to conventional
therapies. With this in mind, we previously demonstrated that
proteolysis targeting chimeras (
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 a
hypoxia-inducing factor 1alpha (HIF-1alpha)-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
PROTAC types. With the pentapeptide linked through the C7alpha position of
estradiol, the resulting
PROTAC shows the most effective ER degradation and highest 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 tumors to conventional drugs such as
tamoxifen and
fulvestrant (
Faslodex).