title: Histone deacetylase inhibitors with a primary amide zinc binding group display antitumor activity in xenograft model.
abstract: Histone deacetylase (HDAC) inhibition causes hyperacetylation of histones leading to differentiation, growth arrest and apoptosis of malignant cells, representing a new strategy in cancer therapy. Many of the known HDAC inhibitors (HDACi) that are in clinical trials possess a hydroxamic acid, that is a strong Zn(2+) binding group, thereby inhibiting some of the class I and class II isoforms. Herein we describe the identification of a selective class I HDAC inhibitor bearing a primary carboxamide moiety as zinc binding group. This HDACi displays good antiproliferative activity against multiple cancer cell lines, and demonstrates efficacy in a xenograft model comparable to vorinostat.
authors.affiliation: IRBM/Merck Research Laboratories, Pomezia, Rome, Italy. thomas_e_barta@yahoo.com
authors.forename: Barbara
authors.initials: B
authors.lastname: Attenni
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000737:chemistry*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases; D015032:Zinc