Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors
| Autor: | Sungmi Park, Inkyu Lee, Injae Shin, Nam Doo Kim, Mi Jin Kim, Taebo Sim, Eun Kyung Yoo, Hojong Yoon, Kyungseon Cho, Hanna Cho |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Pyruvate dehydrogenase kinase
Apoptosis Molecular Dynamics Simulation medicine.disease_cause 01 natural sciences Inhibitory Concentration 50 03 medical and health sciences Cell Line Tumor Neoplasms Drug Discovery Cell Adhesion medicine Humans Enzyme Inhibitors Phosphorylation Cell Proliferation 030304 developmental biology 0303 health sciences Cell growth Kinase Chemistry Pyruvate Dehydrogenase Acetyl-Transferring Kinase Resorcinols Pyruvate dehydrogenase complex Amides 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Biochemistry Cell culture Cancer cell Molecular Medicine Peptides Reactive Oxygen Species Carcinogenesis Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of Medicinal Chemistry. 62:8461-8479 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|