α-Mercaptoketone based histone deacetylase inhibitors

• Published in: Bioorganic & medicinal chemistry 2008-12, Vol.18 (24), p.6482-6485
• Main Authors: Wash, Paul L., Hoffman, Timothy Z., Wiley, Brandon M., Bonnefous, Céline, Smith, Nicholas D., Sertic, Michael S., Lawrence, Charles M., Symons, Kent T., Nguyen, Phan-Manh, Lustig, Kevin D., Guo, Xin, Annable, Tami, Noble, Stewart A., Hager, Jeffrey H., Hassig, Christian A., Malecha, James W.
• Format: Article
• Language: English
• Subjects: Anti-tumor agent; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Chelating Agents - pharmacology; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - pharmacology; General aspects; HeLa Cells; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors; Humans; Ketones - chemistry; Medical sciences; Mercaptoketone; Models, Chemical; Neoplasms - drug therapy; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemistry; SAR; Structure-Activity Relationship; Zinc - chemistry
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.10.058

The identification and lead optimization of a novel series of α-mercaptoketone HDAC inhibitors is described. In an effort to discover novel non-hydroxamic acid histone deacetylase (HDAC) inhibitors, a novel α-mercaptoketone was identified in a high-throughput screen. Lead optimization of the screening hit, led to a number of potent HDAC inhibitors. In particular, α-mercaptoketone 19y (KD5150) exhibited nanomolar in vitro activity and inhibition of tumor growth in vivo.