Structure-Based Optimization of Phenylbutyrate-Derived Histone Deacetylase Inhibitors

摘要

Previously,we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn~(2+)-chelating motifs,which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB),a hydroxamate-tethered phenylbu-tyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation.In this study,we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes.Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization.This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-ll] (IC_(50) in HDAC inhibition,16 nM),of which the isopropyl moiety was favorable in interacting with this hydrophobic motif.(S)-ll at concentrations as low as 0.1 muM was effective in causing histone hyperacetylation and p2l~(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.