Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth

Joel A. Bergman, Karrune Woan, Patricio Perez-Villarroel, Alejandro Villagra, Eduardo M. Sotomayor, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

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 the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.

Original languageEnglish (US)
Pages (from-to)9891-9899
Number of pages9
JournalJournal of medicinal chemistry
Volume55
Issue number22
DOIs
StatePublished - Nov 26 2012

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