Aminosuberoyl hydroxamic acids (ASHAs): A potent new class of HDAC inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 14; pp. 3969 - 3971
• Main Authors: Belvedere, Sandro, Witter, David J., Yan, Jiaming, Secrist, J. Paul, Richon, Victoria, Miller, Thomas A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.07.2007; Elsevier
• Subjects: Animals; Anticancer drug; Antineoplastic agents; Biological and medical sciences; Enzyme Inhibitors - pharmacology; General aspects; HDAC; HDAC inhibitor; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors; Hydroxamic acids; Hydroxamic Acids - pharmacology; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; SAHA; HDAC inhibitor; Anticancer drug; SAHA; Hydroxamic acids; Histone deacetylase inhibitor; HDAC; Antineoplastic agent; Solid tumor; Cytotoxicity; Colon cancer; Structure activity relation; Colon; Chemical synthesis; Anilide; Tumor cell; Erythroleukemia; Human; Enzyme; Aliphatic compound; Acute; Rodentia; Benzene derivatives; Hydroxamic acid; Quinoline derivatives; Enzyme inhibitor; Malignant tumor; In vitro; Colonic disease; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Cell line; Mouse; Animal; Digestive diseases; Carboxamide; Hydrolases; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.04.089

Exploring branched substrate-like HDAC inhibitors, mimicking the peptide substrate, lead to a series of aminosuberoyl hydroxamic acids (ASHAs) with remarkable HDAC inhibitory activity. Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are currently in advanced clinical trials for the treatment of cancer. Vorinostat (Zolinza™, SAHA) is a hydroxamic acid approved for the treatment of patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. As part of an on-going effort to better understand the nature of the HDAC enzyme/inhibitor interaction and design highly effective HDAC inhibitors, we herein report the design, synthesis and HDAC inhibitory activity of a vorinostat-derived series of substrate-based HDAC inhibitors.