Breast cancer is now the most common cancer worldwide and is among the deadliest for women. Approximately 75% of breast cancers are known as estrogen receptor positive (ER+) and express upregulated levels of estrogen receptor alpha (ERα) which has been shown to promote cancer cell proliferation. Current endocrine therapies act by decreasing estrogen biosynthesis using aromatase inhibitors, competing with estrogen for ER binding using tamoxifen, and degrading the ER using fulvestrant. Unfortunately, these hormonal therapies can lead to a significant amount of cancer recurrence with these tumors often exhibiting a newfound drug resistance, thus there is a profound need for alternative treatment. Recent approaches have sought to circumvent endocrine therapy and instead focus on disrupting the interaction between ERα and steroid receptor coactivators (SRCs) using stapled α-helical peptides. A major limitation of stapled peptides is poor cellular uptake without the inclusion of a positively charged poly-arginine sequence which greatly enhances cell permeability at the cost of specificity. Our lab has developed a fluorine-thiol displacement reaction (FTDR) which when paired with our novel fluoroacetamide-containing unnatural amino acid, can staple peptides which display enhanced cellular uptake, stability, and specificity compared to those stapled using the traditional ring-closing metathesis method. Current endocytic mechanism studies have indicated that FTDR stapled peptides can use numerous endocytic pathways to enter cells.

New class of stapled peptides with enhanced cellular uptake targeting estrogen receptor α in breast cancer cells

ACS Spring 2022

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