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

摘要

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 IC50values against both the estrogen receptor α (ERα) and HDACsin vitroand in cell-based assays. The hybrids were antiproliferative against ER+ MCF-7 breast cancer cells, with hybrid28bpossessing an improved activity profile compared to either 4-hydroxytamoxifen or SAHA. Hybrid28bdisplayed gene expression patterns that reflected both ERα and HDAC inhibition.