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

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

  • J Med Chem. 2023 Sep 9. doi: 10.1021/acs.jmedchem.3c01197.
Wenyan She 1,  Tingting Liu 2,  Haimei Li 1,  Zichen Wang 1,  Zhibin Guo 2,  Yi Liu 1 2 3 4,  Yujiao Liu 2
Affiliations

Affiliations

  • 1 College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, P. R. China.
  • 2 State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry & School of Material Science and Engineering, Tiangong University, Tianjin 300387, P. R. China.
  • 3 School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, P. R. China.
  • 4 Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology, Xianning 437100, P. R. China.
PMID: 37688544 DOI: 10.1021/acs.jmedchem.3c01197
Abstract

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.

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