Stapled In the ER
Most breast cancer tumors are estrogen receptor (ER) positive, with common therapies, such as tamoxifen, blocking ER activity. Unfortunately, tumors treated with this type of endocrine therapy relapse or recur in nearly half of all cases. It appears that the function of ER is altered such that, while it retains ER expression, it no longer responds to endocrine therapy. Thomas E. Speltz et al, in ACS Chemical Biology, designed a cell-permeable stapled peptide inhibitor and evaluated its ability to block the estrogen receptor. Stapled peptides are held into a certain conformation, or constrained, by side chain linkages. Due to its constrained nature, a stapled peptide has increased stability, both conformational and proteolytic. Using molecular dynamic simulations, Speltz and team designed the peptide called R4K1, that inhibits the ER/coactivator interaction after being taken up by the breast cancer cells. The ER/coactivator interaction is an alpha-helical protein-protein interaction. The addition of arginine residues increased cell-permeability, and may have also enhanced binding affinity, which was seen through a significant increase in hydrogen bonds formed.1 Hopefully R4K1 will pave the way for additional research on stapled peptide inhibitors for the treatment of ER+ breast cancers.
- T. E. Speltz et al., ACS Chem Biol., 13, 676 (2018).
Endocrine Resistance in Breast Cancer Cells: https://www.pepnet.com/PepTalk/Article/119/Endocrine-Resistance-in-Breast-Cancer-Cells
Past breast cancer features and our products for breast cancer research can be found here: https://www.pepnet.com/site_search.html?query=breast%20cancer