Histone deacetylase inhibitors with a primary amide zinc binding group display antitumor activity in xenograft model

• Published in: Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.3081-3084
• Main Authors: Attenni, Barbara, Ontoria, Jesus M., Cruz, Jonathan C., Rowley, Michael, Schultz-Fademrecht, Carsten, Steinkühler, Christian, Jones, Philip
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; HDAC inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacology; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Primary carboxamide; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Zinc - chemistry; Zinc binding group
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.011

The identification of a selective class I HDAC inhibitor bearing a primary carboxamide as zinc binding group together with its efficacy in vivo is described. 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 Zn2+ 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.