Modulation of the epigenome is understood to be carefully orchestrated by a variety of enzymes, classically describedas a balance of histone acetyltransferases (HATs) and histone deacetylases (HDACs) which act in a state of opposite activity on both histone and non-histone substrates. Widespread inhibition of HDACs, of which there are 11 isoforms comprised of three Zn?2+ classes, can have vast cellular consequences. The role of HDACs are currently being elucidated and individual isoforms are being found to possess unique roles within the cell, as such, there is high interest for the development of isoform-specific HDAC inhibitors (HDACi). Herein we report the development and SAR of branched urea linkers as part of the canonical HDACi scaffold that led to Nexturastat A, a potent and selective HDAC6 inhibitor. Nexturastat A increases  acetyl-tubulin levels and interestingly inhibits the growth of melanoma cells.

Design and development of Nexturastat A, a potent and selective inhibitor of HDAC6

245th National Meeting (2013)

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