Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors.
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.
Schäfer
Stefan
S
Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Germany.
Saunders
Laura
L
Schlimme
Sonja
S
Valkov
Vassil
V
Wagner
Julia M
JM
Kratz
Felix
F
Sippl
Wolfgang
W
Verdin
Eric
E
Jung
Manfred
M
D000409:Alanine / Q000032:analysis* / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry*; D051381:Rats
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C023666:pyridine; D000409:Alanine