Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the inhibition of the enzymatic activity of HDAC4 by small molecules as a novel approach for cancer therapy.
5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC(50) = 310 nM, HDAC6 IC(50) = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2) = 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 microM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.
Ontoria
Jesus M
JM
Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (IRBM-MRL, Rome), Via Pontina Km 30,600, I-00040 Pomezia, Italy. jmontoria@gmail.com
Altamura
Sergio
S
Di Marco
Annalise
A
Ferrigno
Federica
F
Laufer
Ralph
R
Muraglia
Ester
E
Palumbi
Maria Cecilia
MC
Rowley
Michael
M
Scarpelli
Rita
R
Schultz-Fademrecht
Carsten
C
Serafini
Sergio
S
Steinkühler
Christian
C
Jones
Philip
P
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D006657:Histones; D007527:Isoenzymes; D012097:Repressor Proteins; D013876:Thiophenes; D014404:Tubulin; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases