title: VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells.
abstract: Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP competitive pan-isoform inhibitor of PDK, VER-246608. Consistent with a PDK mediated MOA, VER-246608 increased pyruvate dehydrogenase complex (PDC) activity, oxygen consumption and attenuated glycolytic activity. However, these effects were only observed under D-glucose-depleted conditions and required almost complete ablation of PDC E1α subunit phosphorylation. VER-246608 was weakly anti-proliferative to cancer cells in standard culture media; 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.
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK. Current address: Horizon discovery, Cambridge Research Park, Waterbeach, Cambridge, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Staniszewska
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Terence
authors.initials: T
authors.lastname: Shaw
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Jalanie
authors.initials: J
authors.lastname: D'Alessandro
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Surgenor
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Matassova
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Alba
authors.initials: A
authors.lastname: Macias
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brough
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Mahon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000602510:VER-246608; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases