VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells

// Jonathan D. Moore 1,2,* , Anna Staniszewska 1,* , Terence Shaw 1 , Jalanie D’Alessandro 1 , Ben Davis 1 , Alan Surgenor 1 , Lisa Baker 1 , Natalia Matassova 1 , James Murray 1 , Alba Macias 1 , Paul Brough 1 , Mike Wood 1 and Patrick C. Mahon 1 1 Vernalis (RD however, depletion of either serum or combined D-glucose/L-glutamine resulted in enhanced cellular potency. Furthermore, this condition-selective cytostatic effect correlated with reduced intracellular pyruvate levels and an attenuated compensatory response involving deamination of L-alanine. In addition, VER-246608 was found to potentiate the activity of doxorubicin. In contrast, the lipoamide site inhibitor, Nov3r, demonstrated sub-maximal inhibition of PDK activity and no evidence of cellular activity. These studies suggest that PDK inhibition may be effective under the nutrient-depleted conditions found in the tumour microenvironment and that combination treatments should be explored to reveal the full potential of this therapeutic strategy.