Rational design of mitochondria-targeted pyruvate dehydrogenase kinase 1 inhibitors with improved selectivity and antiproliferative activity.

Herein, triphenylphosphonium cation moieties were incorporated into a dichloroacetophenone derivative, leading to the discovery of novel mitochondria-targeted and tumor-specific pyruvate dehydrogenase kinase 1 (PDK1) inhibitors. Biological studies suggested that all these synthesized compounds had significant in vitro activities, in particular compound 1f, which inhibited PDK1 with an EC ₅₀ value of 0.12 μM, and reduced the proliferation of NCI-H1650 cell with an IC ₅₀ value of 0.21 μM, but showed marginal effect against non-cancerous BEAS-2B cell (IC ₅₀  = 3.28 μM). In addition, 1f decreased the extracellular acidification rate and lactate formation, increased reactive oxygen species production, and depolarized the mitochondrial membrane potential of NCI-H1650 cell, which could serve as a potential modulator to reactive mitochondrial oxidative phosphorylation and reprogram the glucose metabolic pathways in cancer cells. Collectively, these data demonstrated that 1f could be a promising lead for the development of therapeutic PDK1 inhibitor in cancer treatment.
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