Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors
- Hanna ChoHanna ChoKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of KoreaMore by Hanna Cho,
- Injae ShinInjae ShinKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of KoreaMore by Injae Shin,
- Kyungseon ChoKyungseon ChoChemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaMore by Kyungseon Cho,
- Hojong YoonHojong YoonChemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaMore by Hojong Yoon,
- Eun Kyung YooEun Kyung YooLeading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of KoreaMore by Eun Kyung Yoo,
- Mi-Jin KimMi-Jin KimLeading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of KoreaMore by Mi-Jin Kim,
- Sungmi ParkSungmi ParkLeading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of KoreaMore by Sungmi Park,
- In-Kyu LeeIn-Kyu LeeLeading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of KoreaDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of KoreaMore by In-Kyu Lee,
- Nam Doo KimNam Doo KimDaegu-Gyeongbuk Medical Innovation Foundation, 2387 Dalgubeol-daero, Suseong-gu, Daegu 42019, Republic of KoreaNDBio Therapeutics Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, Republic of KoreaMore by Nam Doo Kim, and
- Taebo Sim*Taebo Sim*E-mail: [email protected], [email protected]. Phone: +82-2-958-6437.KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaMore by Taebo Sim
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.
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