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Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor‐Targeting PROTACs
Author(s) -
Cyrus Kedra,
Wehenkel Marie,
Choi EunYoung,
Lee Hyosung,
Swanson Hollie,
Kim KyungBo
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000146
Subject(s) - ubiquitin ligase , tamoxifen , estrogen receptor , pentapeptide repeat , agonist , ubiquitin , cancer research , protein degradation , antiestrogen , estrogen receptor alpha , breast cancer , receptor , pharmacology , biology , cancer , microbiology and biotechnology , medicine , biochemistry , peptide , gene
Estrogen receptor‐α (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 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 PROTAC types. With the pentapeptide linked through the C7α 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).