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 EC50 value of 0.12 μM, and reduced the proliferation of NCI-H1650 cell with an IC50 value of 0.21 μM, but showed marginal effect against non-cancerous BEAS-2B cell (IC50 = 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.