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.
Schäfer
Stefan
S
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
Saunders
Laura
L
Eliseeva
Elena
E
Velena
Alfredo
A
Jung
Mira
M
Schwienhorst
Andreas
A
Strasser
Anja
A
Dickmanns
Achim
A
Ficner
Ralf
R
Schlimme
Sonja
S
Sippl
Wolfgang
W
Verdin
Eric
E
Jung
Manfred
M
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