Pyridylalanine‐Containing Hydroxamic Acids as Selective HDAC6 Inhibitors

Abstract

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.

NAD+-dependent histone deacetylases (sirtuins) as novel therapeutic targets

“…58 Therefore, synergistic activity of HDAC and proteasome inhibitors was observed. 59,60 It is yet unclear whether a similar synergy will also be obtained with SIRT2 inhibitors, which also affect tubulin acetylation. The anticancer activity of SIRT2 inhibitors was shown to occur simultaneous to cancer cell inhibition 61 but whether this is symptom or cause remains to be established.…”

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

“…Tubacin binds one of the two catalytic domains of HDAC6 and blocks its function in a-tubulin deacetylation. Jung et al investigated hydroxamates with variable spacer length (C 6 and C 7 ) and various surface recognition elements [239,240]. This study yielded compounds like bromophenyl alanine 61, which showed HDAC6 inhibitory potency in the low micromolar range and modest selectivity over HDAC1.…”

HDAC6: Physiological function and its selective inhibitors for cancer treatment

“…Both of them showed high selectivity and activity. Configuration of this series has also been studied in pyridylalanines compounds, and the research showed us a higher selectivity in compound 8b with an S confi guration (42). The spacer lengh of 6 methylenes was regarded as the best linker for pyridylalanines compounds.…”

“…In the beginning compound 3 was synthesized, then series 4 ( Figure 5) as the analoges of 3 were synthesized. In vitro selectivity and activity towards HDAC6 of the 4 series were tested through immunoprecipitated HDACD1 and HDAC6, and compound 4e with a linker of 7 methylene spacers length and bromophenylalanine 4n with a 6 methylene linker showed high potency and selectivity, and both compounds were also evaluated by Western blot through histone and tubulin acetylation (42). High selectivity of both compounds was revealed with 236 hyperacetylation in the low micromolar range towards tubulin.…”

“…Activity and selectivity of them were also evaluated through immunoprecipitated HDACD1 and HDAC6 and Western blot (42,43). Both of them showed high selectivity and activity.…”