Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors

Qiang Lu, Da Sheng Wang, Chang Shi Chen, Yuan Dong Hu, Ching Shih Chen

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)


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 phenylbutyrate 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)-11] (IC 50 in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 μM was effective in causing histone hyperacetylation and p21WAF/CIP1 overexpression and suppressing proliferation in cancer cells.

Original languageEnglish
Pages (from-to)5530-5535
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number17
Publication statusPublished - 2005 Aug 25

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors'. Together they form a unique fingerprint.

Cite this