ArticleThe Journal of biological chemistry2014
Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 105 citations in OpenAlex.
- FLOWR: flow matching for structure-aware de novo, interaction- and fragment-based ligand generation.Nature computational science · 2026Article
- Small-molecule PS10 inhibits PRRSV replication by targeting HSP90 and multiple viral non-structural proteins.Journal of virology · 2026Article
- Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia.JCI insight · 2025Article
- Hybridization of SMILES and chemical-environment-aware tokens to improve performance of molecular structure generation.Scientific reports · 2025Article
- Pyruvate dehydrogenase kinases: key regulators of cellular metabolism and therapeutic targets for metabolic diseases.Journal of physiology and biochemistry · 2025Review
- Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosisActa pharmaceutica Sinica. B · 2025Article
- Multi-omics derivation of a core gene signature for predicting therapeutic response and characterizing immune dysregulation in inflammatory bowel disease.Frontiers in immunology · 2025Article
- Exploring PDK3 inhibition in lung cancer through drug repurposing for potential therapeutic interventions.Scientific reports · 2024Article
- Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.iScience · 2024Review
- Metabolic inflexibility promotes mitochondrial health during liver regeneration.Science (New York, N.Y.) · 2024Article
- Dichloroacetic acid and rapamycin synergistically inhibit tumor progression.Journal of Zhejiang University. Science. B · 2023Article
- Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target.Frontiers in aging neuroscience · 2023Article
- Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.Journal of lipid and atherosclerosis · 2023Review
- Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy.Cell death & disease · 2022Article
- A Missense Variant inBiomedicines · 2022Article
- Qualitative Estimation of Protein-Ligand Complex Stability through Thermal Titration Molecular Dynamics Simulations.Journal of chemical information and modeling · 2022Article
- Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.International journal of molecular sciences · 2022Review
- Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities.International journal of molecular sciences · 2022Article
- Comparison Between Dichloroacetate and Phenylbutyrate Treatment for Pyruvate Dehydrogenase Deficiency.British journal of biomedical science · 2022Review
- Advanced Bioinformatics Tools in the Pharmacokinetic Profiles of Natural and Synthetic Compounds with Anti-Diabetic Activity.Biomolecules · 2021Review
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Pyruvate dehydrogenase kinase isoforms (PDKs 1-4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure, and cancer and are potential therapeutic targets for these important human diseases. Here, we employed a structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 μM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments pyruvate dehydrogenase complex activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.
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Registered trials
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.