Discovery of pyridone-based histone deacetylase inhibitors: approaches for metabolic stability

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Discovery of pyridone-based histone deacetylase inhibitors: approaches for metabolic stability
M Cho; E Choi; J S Yang; C Lee; J J Seo; B S Kim; Soo Jin Oh; H M Kim; K Lee; S K Park; H J Kwon; G Han
Bibliographic Citation
Chemmedchem, vol. 8, no. 2, pp. 272-279
Publication Year
Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc-dependent HDACs induce proliferation, dedifferentiation, and anti-apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone-based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone-based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam-based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine-based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)-N-hydroxy-3-{1-[3-(naphthalen-2-yl)propyl]-2-oxo-1,2-dihydropyridin-3-yl}acrylamide, exhibited the highest level of HDAC inhibition (IC50=0.07μM), highly selective inhibition of classI HDAC1 and classII HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect invitro activities. Overall, the findings reported herein regarding pyridone-based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.
ConjugationDrug designHistone deacetylasesInhibitorsMetabolismPyridones
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