Histone deacetylase enzymes (HDACs) are one of the best characterised epigenetic targets and two HDAC inhibitors (Vorinostat and Romidepsin) are FDA approved for the treatment of cancer. Abnormal HDAC activity is associated with a variety of other diseases, but the therapeutic use of HDAC inhibitors is currently limited by high toxicity which is likely due to off target effects and a lack of isoform selectivity. We designed and synthesised a novel series of potent chiral HDAC inhibitors that contain a heterocyclic capping group and an N-(2-aminophenyl) benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl) benzamide 1  gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1.

Synthesis of novel isoform selective histone deacetylase inhibitors containing chiral heterocyclic capping groups

248th National Meeting (2014)

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