Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy

In many types of cancers, pyruvate dehydrogenase kinase
(PDK) is
abnormally overexpressed and has become a promising target for cancer
therapy. However, few highly effective inhibitors of PDK have been
reported to date. Herein, we designed and synthesized a series of
PDK inhibitors based on dichloroacetate (DCA) and arsenicals. Of the
27 compounds, 1f demonstrated PDK inhibition with high
efficiency at a cellular level (IC50 = 2.0 μM) and
an enzyme level (EC50 = 68 nM), far more effective than
that of DCA. In silico, in vitro, and in vivo studies demonstrated that 1f inhibited PDK, shifted the energy metabolism from aerobic glycolysis
to oxidative phosphorylation, and induced cell apoptosis. Moreover,
new 1f-loaded nanoparticles were developed, and the administration
of high-drug-loading nanoparticles (0.15 mg/kg) caused up to 90% tumor
shrinkage without any apparent toxicity. Hence, this study provided
a novel metabolic therapy for cancer treatment.