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  • [J Med Chem.] Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors.

    고려대 / 조한나, 신인재, 심태보*

  • 출처
    J Med Chem.
  • 등재일
    2019 Sep 26
  • 저널이슈번호
    62(18):8461-8479. doi: 10.1021/acs.jmedchem.9b00565. Epub 2019 Sep 13.
  • 내용

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    Abstract
    Pyruvate dehydrogenase kinases (PDHKs) promote abnormal respiration in cancer cells. Studies with novel resorcinol amide derivatives based on VER-246608 (6) led to the identification of 19n and 19t containing five-membered heteroaromatic rings as unique structural features. These substances possess single-digit nanomolar activities against PDHKs. 19t exhibits higher potencies against PDHK1/2/4 than does 6 and inhibits only PDHKs among 366 kinases. Moreover, 19g, 19l, and 19s were found to be isotype-selective PDHK inhibitors. Molecular dynamics simulations provide a better understanding of how the heteroaromatic rings affect the activities of 19n and 19t on PDHK1/2/3/4. Moreover, 19n possesses a much higher antiproliferative activity against cancer cells than does 6. We demonstrated that the results of PDH assays better correlate with cellular activities than do those of PDHK kinase assays. Furthermore, 19n induces apoptosis of cancer cells via mitochondrial dysfunction, suppresses tumorigenesis, and displays a synergistic effect on satraplatin suppression of cancer cell proliferation.

     


    Author information

    Cho H1, Shin I1, Cho K2, Yoon H2, Yoo EK3, Kim MJ3, Park S3, Lee IK3,4, Kim ND5,6, Sim T1,2.
    1
    KU-KIST Graduate School of Converging Science and Technology , Korea University , 145 Anam-ro , Seongbuk-gu, Seoul 02841 , Republic of Korea.
    2
    Chemical Kinomics Research Center , Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil , Seongbuk-gu, Seoul 02792 , Republic of Korea.
    3
    Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease , Kyungpook National University Hospital , Daegu 41404 , Republic of Korea.
    4
    Department of Internal Medicine, School of Medicine, Kyungpook National University , Kyungpook National University Hospital , Daegu 41944 , Republic of Korea.
    5
    Daegu-Gyeongbuk Medical Innovation Foundation , 2387 Dalgubeol-daero , Suseong-gu, Daegu 42019 , Republic of Korea.
    6
    NDBio Therapeutics Inc. , 32 Songdogwahak-ro , Yeonsu-gu, Incheon 21984 , Republic of Korea.

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