Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors.

Abstract

Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 103 M-1 s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.

• Authors: Yifu Liu, Zuoquan Xie, Dan Zhao, Jin Zhu, Fei Mao, Shuai Tang, Hui Xu, Cheng Luo, Meiyu Geng, Min Huang, Jian Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 6 Pg. 2227-2244 (03 23 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28230989 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Disulfides
• Morpholines
• PDK1 protein, human
• PDK2 protein, human
• Pdk1 protein, mouse
• Pdk2 protein, mouse
• Protein Kinase Inhibitors
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• bis(4-morpholinyl thiocarbonyl)disulfide
• Protein Serine-Threonine Kinases
• Glucose

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Disulfides (chemistry, pharmacology, therapeutic use)
• Female
• Glucose (metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Molecular Docking Simulation
• Morpholines (chemistry, pharmacology, therapeutic use)
• Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (chemistry, pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase