ArticleOncotarget2014
VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells.
Article in Oncotarget, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 59 citations in OpenAlex.
- Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors.Acta pharmaceutica Sinica. B · 2026Review
- Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).Cell communication and signaling : CCS · 2026Review
- Hybridization of SMILES and chemical-environment-aware tokens to improve performance of molecular structure generation.Scientific reports · 2025Article
- PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma.Cell death & disease · 2025Article
- Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer.Cancers · 2023Article
- Thermal Titration Molecular Dynamics (TTMD): Not Your Usual Post-Docking Refinement.International journal of molecular sciences · 2023Article
- Qualitative Estimation of Protein-Ligand Complex Stability through Thermal Titration Molecular Dynamics Simulations.Journal of chemical information and modeling · 2022Article
- Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity-related cell death in A549 non-small cell lung cancer cells.BMB reports · 2021Article
- Article
- Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications.Bioscience reports · 2021Review
- Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity.Scientific reports · 2020Article
- Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures.Communications chemistry · 2020Article
- Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds.Biomolecules · 2019Article
- Discovery of potent pyruvate dehydrogenase kinase inhibitors and evaluation of their anti-lung cancer activity under hypoxia.MedChemComm · 2018Article
- Targeting energy metabolism to eliminate cancer cells.Cancer management and research · 2018Review
- Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.Journal of medicinal chemistry · 2017Article
- Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.Scientific reports · 2017Article
- Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells.PloS one · 2017Article
- Pyruvate dehydrogenase kinase regulates hepatitis C virus replication.Scientific reports · 2016Article
- MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.