Incorporation of histone deacetylase inhibitory activity into the core of tamoxifen - A new hybrid design paradigm.

Abstract

Hybrid antiestrogen/histone deacetylase (HDAC) inhibitors were designed by appending zinc binding groups to the 4-hydroxystilbene core of 4-hydroxytamoxifen. The resulting hybrids were fully bifunctional, and displayed high nanomolar to low micromolar IC50 values against both the estrogen receptor α (ERα) and HDACs in vitro and in cell-based assays. The hybrids were antiproliferative against ER+ MCF-7 breast cancer cells, with hybrid 28b possessing an improved activity profile compared to either 4-hydroxytamoxifen or SAHA. Hybrid 28b displayed gene expression patterns that reflected both ERα and HDAC inhibition.

• Authors: Anthony F Palermo, Marine Diennet, Mohamed El Ezzy, Benjamin M Williams, David Cotnoir-White, Sylvie Mader, James L Gleason
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 15 Pg. 4428-4440 (08 15 2018) ISSN: 1464-3391 [Electronic] England
• PMID: 30078609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• ESR1 protein, human
• Estrogen Antagonists
• Estrogen Receptor alpha
• Histone Deacetylase Inhibitors
• Isoenzymes
• Tamoxifen
• Histone Deacetylases
• Zinc

Topics

• Binding Sites
• Cell Proliferation (drug effects)
• Drug Design
• Estrogen Antagonists (chemistry)
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Histone Deacetylase Inhibitors (chemistry)
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Inhibitory Concentration 50
• Isoenzymes (antagonists & inhibitors, metabolism)
• MCF-7 Cells
• Molecular Docking Simulation
• Protein Structure, Tertiary
• Tamoxifen (chemical synthesis, chemistry, pharmacology)
• Zinc (chemistry)