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).
Department of Pharmaceutical Sciences, University of Kentucky, 789 South Limestone, Lexington, KY 40536-0596, USA.
Kedra
K
Cyrus
Marie
M
Wehenkel
Eun-Young
EY
Choi
Hyosung
H
Lee
Hollie
H
Swanson
Kyung-Bo
KB
Kim
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
C405619:HIGD1A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011960:Receptors, Estrogen; D004958:Estradiol; D051794:Von Hippel-Lindau Tumor Suppressor Protein