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

  • Bioorg Med Chem. 2018 Aug 15;26(15):4428-4440. doi: 10.1016/j.bmc.2018.07.026.
Anthony F Palermo  1 ,  Marine Diennet  2 ,  Mohamed El Ezzy  2 ,  Benjamin M Williams  1 ,  David Cotnoir-White  2 ,  Sylvie Mader  3 ,  James L Gleason  4
Affiliations
  • 1. Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada.
  • 2. Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, QC H3T 1J4, Canada.
  • 3. Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, QC H3T 1J4, Canada; Biochemistry Department, Pavillon Roger-Gaudry, Université de Montréal, 2900 Bd Edouard Montpetit, Montréal, QC H3T 1J4, Canada; Centre de Recherche du CHUM, Université de Montréal, Montréal, QC H2X 0A9, Canada.
  • 4. Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada. Electronic address: [email protected].
PMID: 30078609 DOI: 10.1016/j.bmc.2018.07.026
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.

Keywords
Antiestrogens; Breast cancer; Histone deactylase inhibitors; Hybrid molecules.