title: 2-Trifluoroacetylthiophenes, a novel series of potent and selective class II histone deacetylase inhibitors.
abstract: The identification of class II HDAC inhibitors has been hampered by lack of efficient enzyme assays, in the preceding paper two assays have been developed to improve the efficiency of these enzymes: mutating an active site histidine to tyrosine, or by the use of a trifluoroacetamide lysine substrate, allowing screening to identify class II HDAC inhibitors. Herein, 2-trifluoroacetylthiophenes have been demonstrated to inhibit class II HDACs, resulting in the development of a series of 5-(trifluoroacetyl)thiophene-2-carboxamides as novel, potent and selective class II HDAC inhibitors. X-ray crystal structures of the HDAC 4 catalytic domain with a bound inhibitor demonstrate these compounds are active site inhibitors and bind in their hydrated form.
authors.affiliation: IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy. philip_jones@merck.com
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfí
authors.forename: Ottavia
authors.initials: O
authors.lastname: Cecchetti
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
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: Christian
authors.initials: C
authors.lastname: Steinkühler
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D013876:Thiophenes; D006655:Histone Deacetylases; D015032:Zinc