Histone deacetylase enzymes (HDACs) are emerging as important therapeutic targets in cancer. These enzymes regulate gene expression by modulating chromatin lysine actylation state. Removal of an acetyl group from lysine results in chromatin condensation and a concomitant reduction in gene transcription. Full enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are subsequently recruited to chromatin by repressive transcription factors. Recently the structure of a complex between human HDAC3 and the deacetylase activation domain (DAD) from the human SMRT co-repressor has been reported.[1] Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/240nm/uploads/32613_figure1.jpg' alt='' /> This structure reveals two remarkable features: firstly, the SMRT-DAD undergoes a large structural rearrangement on forming the complex; secondly, D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P4) mediates that protein-protein interaction, acting as an 'intermolecular glue' between the two proteins. As assembly of the complex is dependent on Ins(1,4,5,6)P4, it seems likely that this small molecule has a regulatory role in HDAC3 function�potentially explaining the link between inositol phosphates kinases and transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and presents novel therapeutic opportunities. To understand and establish the role played D-myo-inositol-(1,4,5,6)-tetrakisphosphate in mediating protein-protein interactions in the regulation of HDAC1 and 3 activity, the synthesis of P1- and P4-modified Ins(1,4,5,6)P4 derivatives acting as potential selective HDAC1 and 3 inhibitors will be presented.[1] Watson P. J. and all. Nature, 2012 , 481, 335�340

Synthesis of inositol-(1,4,5,6)-tetrakisphosphate�based probes for HDAC3 function

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.