title: 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.
abstract: 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.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (IRBM-MRL, Rome), Via Pontina Km 30,600, I-00040 Pomezia, Italy. jmontoria@gmail.com
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Annalise
authors.initials: A
authors.lastname: Di Marco
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Sergio
authors.initials: S
authors.lastname: Serafini
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: 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
chemical_list: 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