On April 29, 2009 Crystal Genomics reported Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes (Press release, CrystalGenomics, APR 29, 2009, View Source;id=596&page=10&num=27&nowpos=1252&type=&sermun=&qu=&tb_name=eng_news&rt_page=/en/news/news.php [SID1234539172]). Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the side chain of lysine of core nucleosomal histones. This posttranslational modification of core histone is involved in the regulation of the transcriptional activity of certain genes. It has been known that aberrant recruitment of HDAC activity is associated with the development of certain human cancers.
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In this study, we have discovered series of HDAC inhibitors by using the structure-based drug discovery technologies. The optimized compounds were evaluated by various enzyme inhibitory assays, anti-proliferation assays against cancer cell lines, FACS analysis and measurement of acetylated histone accumulation. We also carried out in vitro ADME studies including metabolic stability, CYP inhibition assays, and in vivo PK studies. The anti-tumor efficacy was also tested in the various xenograft tumor model. Many of them showed clear anti-tumor effects. Among them, CG200745 showed promising anti-tumor profiles. CG200745 inhibits histone deacetylase activity in low range nM of IC50 against class 1 and class II HDACs. The CG200745 exhibited a broad spectrum of anti-proliferative activity against various cancer cell lines at sub micromolar EC50. Mechanistically, the CG200745 induced dose -dependent increase in the accumulation of acetylated histone H4 and in apoptosis supported by annexin-V analysis in various tumor cell lines. CG200745 also showed potent antitumor effect in various xenograft tumor model.
In addition, the preclinical safety studies of CG200745 were performed in rodent and non-rodent systems for dose determination of first in human trial.
In conclusion, CG200745, novel HDAC inhibitors that are discovered through the structure based drug discovery, show potent anti-tumor activity in cell-based assays and animal studies. Currently, further PK/PD studies and preclinical safety studies of CG200745 are in progress