Characterization of CG-781, a potent histone deacetylase inhibitor, as a cancer therapeutic

1801 Histone acetylation is one mechanism by which chromatin structure and its transcription is regulated. Transcriptionally active chromatin regions are associated with hyperacetylated histones and transcriptionally silent chromatin regions are associated with hypoacetylated histones. Histone deacetylases (HDACs) and histone acetyltransferases thus play a crucial role in regulating chromatin structure and gene expression. One of the hallmarks of human neoplasia is aberrant gene expression (the activation of genes for proliferation and the silencing of tumor suppressors). Because of its role(s) in chromatin remodeling and transcriptional regulation, HDAC inhibitors are being evaluated as anti-cancer therapeutics. Here we present data on CG-781 on its activities as an HDAC inhibitor and as an anti-cancer agent. CG-781 has displayed potent activity against recombinant human HDAC enzymes in vitro. It has exhibited sub-μM growth-inhibitory activities in vitro against an array of human cancer cell lines. Examination of CG-781 in vivo has revealed significant anti-tumor activity against different tumor xenografts. Statistically significant tumor growth inhibition at 80+% and 40+% has been achieved with CG-781 against HCT 116 & DLD-1 respectively. Anti-tumor activity was observed with different pre-clinical dosing regimens, and also with either intravenous or intraperitoneal delivery. Pharmacodynamic evaluation of circulating blood cells and tumor samples revealed that protein acetylation correlates with drug exposure. Gene expression profiling over various doses and timepoints has identified a robust set of genes whose expression in tumors is affected by treatment with CG-781. Similar analysis of whole blood samples from the same mice has also provided a set of marker genes that track with efficacy. Continued analysis and validation of target genes regulated by CG-781 could provide greater insight into the mechanism of action for CG-781 and potentially facilitate its clinical application.