Histone deacetylases (HDACs) covalently modify e-N-acetylated lysines on histone tails and contribute to regulation of gene activation. Dysfunction of the enzymes is known to be related to many cancer forms. Over the last decade it has been recognized that a whole range of non-histone proteins are substrates to this family of enzymes and HDAC dysfunction is observed in a number of clinical conditions beside cancers, such as neurodegenerative disorders, memory loss, and cystic fibrosis. HDAC inhibitors, which can assist in rectifying such dysfunction is therefore an interesting target for drug development1.In the work presented here, scaffolds from known medicinally relevant HDAC inhibitors were the basis for a small array of potential HDAC inhibitors which were synthesized and profiled. The classical pharmacophore of HDAC inhibitors includes a capping group, a linker and a zinc binding group. The library was designed to compare novel zinc binding groups as well as zinc binding groups from established toolboxes. Silanediol and sulfonamides among other were incorporated as novel zinc binding groups which were compared to ketones, trifluoromethyl ketones, hydroxamic and carboxylic acids in the library. The compounds were tested in vitro against the full panel of recombinant human HDACs and expanded the current arsenal of zinc binding motifs for future design of HDAC inhibitors2.1. Arrowsmith, C. H.; Bountra, C.; Fish, P. V.; Lee, K.; Schapira, M., Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 2012,  11 (5), 384-400.2. Madsen, A. S.; Kristensen, H. M. E.; Lanz, G.; Olsen, C. A., The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1�11. ChemMedChem 2014,  9 (3), 614-626.

Inhibitory effect of various zinc binding groups on HDAC1�11

248th National Meeting (2014)

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