Reversing the Warburg effect: Discovery of potent pyruvate dehydrogenase kinase inhibitors for inhibiting tumor growth.

Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in tumors, driving cancer progression by promoting the Warburg effect. Consequently, PDK1 inhibition represents a promising anticancer strategy, though potent low-toxicity inhibitors remain scarce. In this study, 20 new derivatives were designed and synthesized through further structural optimization of the dichloroacetate (DCA) derivatives, and their inhibitory effects on PDK1 and anticancer activities were systematically evaluated. Compound D16 emerged as the lead candidate, demonstrating potent PDK1 inhibition (53.20 % at 1 μM), significant suppression of cancer cells proliferation (A549 IC50 = 0.86 μM) and migration. Notably, D16 reverses the Warburg effect, shifting cellular energy metabolism from glycolysis toward oxidative phosphorylation, evidenced by increased acetyl-CoA, reduced lactate, elevated ROS, and induced apoptosis. Importantly, low-dose D16 (20 mg/kg) robustly inhibited tumor growth in vivo without systemic toxicity. These findings establish D16 as a potent PDK1 inhibitor that shifts tumor metabolism, offering a promising therapeutic approach for cancer treatment.