Selective Histone Deacetylase 6 Inhibitors Bearing Substituted Urea Linkers Inhibit Melanoma Cell Growth

• DOI: 10.1021/jm301098e
• Publication Date: 2012-09-25T16:49:20Z
• Authors: Joel A. Bergman; Karrune Woan; Patricio Perez-Vi...; Alejandro Villagra; Eduardo M. Sotomayor; Alan P. Kozikowski
• Keywords: HDAC6; Linker; Structure–activity relationship

The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed adding substituents nitrogen atom so as generate compounds bearing branched linker group results potency and selectivity HDAC6. Compound 5 g shows low nanomolar inhibitory against HDAC6 ∼600-fold relative inhibition HDAC1. These HDACIs were evaluated their ability inhibit growth B16 cells with most HDAC6I being found decrease tumor cell growth. To best knowledge, this work constitutes first report HDAC6-selective possess antiproliferative effects cells.