A Cell-Permeable Stapled Peptide Inhibitor of the Estrogen Receptor/Coactivator Interaction

ACS Chemical Biology
Thomas E SpeltzTerry W Moore

Abstract

We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer. To accomplish this, we used molecular dynamics simulations to convert a high-affinity stapled peptide with poor cell permeability into R4K1, a cell-penetrating stapled peptide. R4K1 displays high binding affinity for estrogen receptor α, inhibits the formation of estrogen receptor/coactivator complexes, and distributes throughout the cell with a high percentage of nuclear localization. R4K1 represses native gene transcription mediated by estrogen receptor α and inhibits proliferation of estradiol-stimulated MCF-7 cells. Using RNA-Seq, we demonstrate that almost all of the effects of R4K1 on global gene transcription are estrogen-receptor-associated. This chemical probe provides a significant proof-of-conc...Continue Reading

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Citations

Dec 5, 2018·Chembiochem : a European Journal of Chemical Biology·May BakailAndrew J Wilson
May 26, 2020·Archiv der Pharmazie·Rajeev KharbMohammad S Yar
May 5, 2018·Organic & Biomolecular Chemistry·Thomas E SpeltzTerry W Moore
Aug 9, 2019·Chemical Science·Fatemeh M MirWilliam D Lubell
Jun 5, 2019·Molecular and Cellular Endocrinology·Kornelia J SkowronTerry W Moore
Jul 24, 2018·ACS Medicinal Chemistry Letters·Brian P DavidTerry W Moore
Jan 9, 2020·ACS Combinatorial Science·Olivier B C MontyNicholas Simmons
May 16, 2019·Chemical Reviews·Patrick G DoughertyDehua Pei
Sep 4, 2018·Journal of the American Chemical Society·Curran A RhodesDehua Pei

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