Pyridylalanine-Containing Hydroxamic Acids as Selective HDAC6 Inhibitors

Pyridylalanine inhibitors of histone deacetylase (HDAC) have been synthesized that show selectivity for the isoform HDAC6 over HDAC1 in vitro. This selectivity was also identified in cancer cells by analyzing tubulin versus histone acetylation. The compounds show decreased intrinsic cytotoxicity relative to pan-HDAC inhibitors, but show antiproliferative synergy with the proteasome inhibitor bortezomib. We synthesized hydroxamic acids with a pyridylalanine substructure and identified them as selective inhibitors of human recombinant HDAC6. The in vitro selectivity was up to 25-fold for HDAC6 over HDAC1 and was confirmed by Western blotting to assess tubulin versus histone acetylation in cancer cells. Docking studies with an HDAC6 homology model suggested that the hydrophobic cap group of the inhibitors interacts with aromatic residues that form a sub-pocket near the entrance of the substrate binding channel. The HDAC6-selective compounds have less cytotoxicity toward cancer cells than do pan-HDAC inhibitors. The synergistic antiproliferative activity we showed with the proteasome inhibitor bortezomib suggests the potential for combination anticancer therapy with less general toxicity.