Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted...

Area of Science:

• Biochemistry
• Oncology
• Drug Discovery

Background:

• Pyruvate dehydrogenase kinase (PDK) is overexpressed in many cancers, making it a key therapeutic target.
• Existing PDK inhibitors lack high efficacy, necessitating the development of novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel dichloroacetate (DCA)- and arsenical-based pyruvate dehydrogenase kinase (PDK) inhibitors.
• To evaluate the efficacy of these inhibitors in preclinical cancer models.
• To develop nanoparticle formulations for improved drug delivery and therapeutic outcomes.

Main Methods:

• Synthesis and characterization of 27 novel compounds.
• In vitro enzyme inhibition assays and cellular assays to determine IC50 and EC50 values.
• In silico, in vitro, and in vivo studies to assess mechanism of action and therapeutic effects.
• Development and evaluation of 1f-loaded nanoparticles for cancer treatment.

Main Results:

• Compound 1f exhibited potent PDK inhibition at both enzyme (EC50 = 68 nM) and cellular (IC50 = 2.0 μM) levels, significantly outperforming DCA.
• 1f treatment shifted cancer cell metabolism from aerobic glycolysis to oxidative phosphorylation and induced apoptosis.
• High-drug-loading 1f nanoparticles achieved up to 90% tumor shrinkage with no apparent toxicity in vivo.

Conclusions:

• The novel compound 1f is a highly effective PDK inhibitor with significant therapeutic potential for cancer treatment.
• 1f-loaded nanoparticles offer a promising strategy for targeted cancer therapy, demonstrating potent tumor regression and safety.
• This study presents a novel metabolic therapy approach for cancer, highlighting the therapeutic value of targeting PDK.