Histone deacetylases (HDACs) are epigenetic regulators that regulate the histone tail, chromatin conformation, protein-DNA interaction, and even transcription. HDACs are also post-transcriptional modifiers that regulate the protein acetylation implicated in several pathophysiologic states[1]. EDO-S101, a pan HDAC inhibitor, inhibits HDAC6, HDAC1, HDAC2 and HDAC3 with IC50 values of 6 nM, 9 nM, 9 nM and 25 nM, respectively. EDO-S101 (10 mg/kg i.v.; 1 h) inhibited HDAC activity in rat PBMCs in a cellular assay by approximately 90%. in HL60 and MM1S Cells, EDO-S101 demonstrated significant acetylation of lysine residues, further confirming the HDAC-inhibition function of the vorinostat moiety in the EDO-S101 molecule. Alkylation was evaluated in vitro in myeloid (HL60 AML cell line) and lymphoid cell lines. EDO-S101 caused DNA cross links in the Comet assay at low concentrations demonstrating the alkylating function of the molecule. Exposure to EDO-S101 in vivo caused a strong DNA repair response evidenced by activation of pH2AX and p53 in tumors taken from mice bearing subcutaneous human Burkitt’s lymphoma. Moreover, 4 μM EDO-S101 triggered apoptosis in vitro and in vivo, resulting in strong antitumor activity in HL60 and Daudi cells and in the Daudi xenograft model[2].
搜索
