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

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.

• Authors: Hanna Cho, Injae Shin, Kyungseon Cho, Hojong Yoon, Eun Kyung Yoo, Mi-Jin Kim, Sungmi Park, In-Kyu Lee, Nam Doo Kim, Taebo Sim
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 18 Pg. 8461-8479 (09 26 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 31469962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Enzyme Inhibitors
• Peptides
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Reactive Oxygen Species
• Resorcinols
• resorcinol

Topics

• Amides (chemistry, pharmacology)
• Apoptosis
• Cell Adhesion
• Cell Line, Tumor
• Cell Proliferation
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Inhibitory Concentration 50
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Neoplasms (drug therapy, enzymology)
• Peptides (chemistry)
• Phosphorylation
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase (antagonists & inhibitors, chemistry)
• Reactive Oxygen Species (metabolism)
• Resorcinols (chemistry, pharmacology)