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Updated: Jul 9, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK
Linling Gan1, Ying Yang2, Zizhen Liang2
1Chongqing Engineering Research Center of Pharmaceutical Sciences, School of Pharmacy, Chongqing Medical and Pharmaceutical College, Chongqing, 401331, PR China.
Abstract:
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 (IC50 = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC50 = 8.67 μM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC50 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.
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