Design, synthesis and antiproliferative activity of raloxifene/histone deacetylase inhibitor hybrids in breast cancer

Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, 21 (YW471), 22 (YW490), 27(YW486), and 28 (YW487) showed good potency both as antiestrogens in a BRET assay and in a fluorometric HDACi assay. The antiproliferative activity of the hybrids was demonstrated in both ER+ MCF7 and ER– MDA-MB-231 breast cancer cell lines. [Display omitted] •Hybrid molecules based on raloxifene and HDAC inhibitors were designed and synthesized.•Hybrids are fully bifunctional, possessing nanomolar antiestrogen activity and HDAC inhibition in both in vitro and cellular assays.•First example of incorporating HDAC inhibition in the part of raloxifene that binds within the ER ligand binding pocket.•Hybrids provide more complete inhibition of growth of ER + MCF7 cells and possess activity against ER– MDA-MB-231 cells.