Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases (HDACs).
We synthesized biarylalanine-containing hydroxamic acids and tested them on immunoprecipitated HDAC1 and HDAC6 and show a subtype selectivity for HDAC6 that was confirmed in cells by Western blot (tubulin vs histones). We obtained an X-ray structure with a HDAC6-selective inhibitor with the bacterial deacetylase HDAH. Docking studies were carried out using HDAC1 and HDAC6 protein models. Antiproliferative activity was shown on cancer cells for selected compounds.
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
Stefan
S
Schäfer
Laura
L
Saunders
Elena
E
Eliseeva
Alfredo
A
Velena
Mira
M
Jung
Andreas
A
Schwienhorst
Anja
A
Strasser
Achim
A
Dickmanns
Ralf
R
Ficner
Sonja
S
Schlimme
Wolfgang
W
Sippl
Eric
E
Verdin
Manfred
M
Jung
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D010649:Phenylalanine; D011485:Protein Binding; D014404:Tubulin
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014404:Tubulin; D010649:Phenylalanine; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases