text: Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs.
  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).
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T3 T4 T5 T6 T7 T8 T9
entities.type: CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: estrogen Estrogen receptor-alpha E3 ubiquitin ligase von Hippel Lindau tumor suppressor protein pVHL ER E3 ligase ER ER estrogen receptor Estrogen ER ER ER ER ER ER ER ER ER hypoxia-inducing factor 1alpha estradiol HIF-1alpha estrogen receptor estradiol estrogen tamoxifen fulvestrant Faslodex tamoxifen estradiol