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Discovery of Pyridone-Based Histone Deacetylase Inhibitors: Approaches for Metabolic Stability

Authors

  • Misun Cho,

    1. Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
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  • Dr. Eunhyun Choi,

    1. Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, Seodaemun-Gu, Seoul 120-752 (Republic of Korea)
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  • Dr. Jee Sun Yang,

    1. Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
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  • Dr. Chulho Lee,

    1. Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
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  • Jeong Jea Seo,

    1. Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
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  • Beom Seok Kim,

    1. TRCP, Chemical Genomics National Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seodeamun-gu, Seoul 120-749 (Republic of Korea)
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  • Dr. Soo Jin Oh,

    1. Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Yangcheong, Ochang, Cheongwon, Chungbuk 363-883 (Republic of Korea)
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  • Prof. Hwan Mook Kim,

    1. College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799 (Republic of Korea)
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  • Prof. Kiho Lee,

    1. College of Pharmacy, Korea University, Yeongi, Chungnam 339-700 (Republic of Korea)
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  • Prof. Song-Kyu Park,

    1. College of Pharmacy, Korea University, Yeongi, Chungnam 339-700 (Republic of Korea)
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  • Prof. Ho Jeong Kwon,

    1. TRCP, Chemical Genomics National Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seodeamun-gu, Seoul 120-749 (Republic of Korea)
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  • Prof. Gyoonhee Han

    Corresponding author
    1. Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
    • Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749 (Republic of Korea)
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Abstract

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=0.07 μM), highly selective inhibition of class I HDAC1 and class II 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 in vitro 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.

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