Discovery of potent pyruvate dehydrogenase kinase inhibitors and evaluation of their anti-lung cancer activity under hypoxia

Targeting pyruvate dehydrogenase kinases (PDKs) reverses the Warburg effect, which could be a potential therapeutic target for anti-cancer drug discovery. In this paper, we identified 12 potential PDK inhibitors by virtual ligand screening of a chemical library, and then further verified them by an enzymatic assay, in which 6, 7, and 11 strongly inhibited the function of PDKs, with IC(50) values of 1.26, 0.62, and 0.41 μM against PDK1, respectively, and showed a similar inhibitory effect on PDK2, PDK3, and PDK4. However, we failed to correlate the observed inhibitory activity against PDKs with cellular activity under normal conditions. In contrast, 7 and 11 inhibited NCI-H1975 cell proliferation under hypoxia, with EC(50) values of 4.66 and 3.88 μM, respectively, suggesting that 7 and 11 could be promising leads for further development of PDK inhibitors in cancer treatment.