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 IC50 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 EC50 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.