Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation

• Published in: European journal of medicinal chemistry 2024-01, Vol.264, p.116008-116008, Article 116008
• Main Authors: Gan, Linling, Yang, Ying, Liang, Zizhen, Zhang, Maojie, He, Yun, Zhang, Shao-Lin
• Format: Article
• Language: English
• Subjects: Cell Division; Oxidative Phosphorylation; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; Pyruvate Dehydrogenase Complex - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.116008

Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis. We successfully identified 6 compounds from a small molecule library through a structure-based virtual screening campaign and evaluated their enzymatic inhibitory potencies for PDK1-4. Our results indicated that compound 1 exhibited submicromolar inhibitory activities against PDK1-3 (IC  = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC  = 8.67 μM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC value of 10.7 μM. In addition, compound 1 induced cell apoptosis, arrested the cell cycle at the S phase, and reduced cell invasion and migration, while showing low in vivo toxicity at a high dose. Based on these observations, it can be concluded that compound 1 is a promising anti-PDK1-3 lead that merits further investigation.