Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors

Hanna Cho, Injae Shin, Kyungseon Cho, Hojong Yoon, Eun Kyung Yoo, Mi Jin Kim, Sungmi Park, In Kyu Lee, Nam Doo Kim, Taebo Sim

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5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)8461-8479
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - 2019 Sept 26

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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