Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors

Abstract

Histone deacetylases (HDACs) are epigenetic enzymes involved in regulation of histone posttranslational modifications and gene expression. Since changed function of HDACs is involved in pathogenesis of cancer 1-3, the HDAC inhibitors are extensive examined as promising anticancer agents. In our in silico study we have combined structure-based, ligand-based, and fragment-based methodologies to design selective inhibitors against cytoplasmic isoforms of HDAC, such as histone deacetylase 6 inhibitors (HDAC6) and SIRT2. The drug design study has defined several promising selective HDAC6 and SIRT2 inhibitors for further synthesis and in vitro testing. Based on the in vitro activities of the novel compounds in a panel of biochemical HDAC assays as well as various cell-based assays were selected the most promising candidates for further investigation.