ArticleThe Journal of biological chemistry2014
Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase.
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 71 papers, 1 of them a synthesis that pooled it.
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 105 citations in OpenAlex.
- Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.PLoS medicine · 2016Pooled it
- A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes.Nature communications · 2022Trial
- Discovery urinary metabolomics of preterm neonatal acute kidney injury.Pediatric nephrology (Berlin, Germany) · 2026Observational
- The emerging role of branched-chain amino acid metabolism in obesity.International journal of obesity (2005) · 2026Review
- Impaired Lung BCAA Metabolism Promotes Ferroptosis and Resultant Pulmonary Arterial Hypertension-Associated Hepatopathy.JACC. Basic to translational science · 2026Article
- GRSF1 Protects Against Heart Failure by Maintaining BCAA Homeostasis.Circulation · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- Review
- Angel or demon? The dual role of branched-chain amino acids in chronic inflammatory and injury-related diseases.Frontiers in immunology · 2026Review
- BCAAs and related metabolic enzymes: partners in crime driving tumor development.Frontiers in cell and developmental biology · 2026Review
- Branched-chain amino acid metabolism and macrophage polarization: potential regulatory nodes and therapeutic targets in diabetes-associated metabolic inflammation.Frontiers in cellular and infection microbiology · 2026Review
- Multimodal Therapeutic Strategies Targeting BCAA Metabolism in Diabetic Cardiomyopathy: A Path to Cardioprotection.Cardiovascular toxicology · 2025Review
- Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Article
- Branched-Chain α Keto-Acid Dehydrogenase Kinase-Mediated AKT Phosphorylation Promotes RCC Tumorigenesis and Drug Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential.Cell death discovery · 2025Review
- Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis.Nature communications · 2025Article
- Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.Molecular metabolism · 2025Article
- Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy.Biomolecules · 2025Review
- HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.Science advances · 2025Article
- Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
11 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
The mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC) is negatively regulated by reversible phosphorylation.BCKDC kinase (BDK) inhibitors that augment BCKDC flux have been shown to reduce branched-chain amino acid (BCAA) concentrations in vivo. In the present study, we employed high-throughput screens to identify compound 3,6- dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) as a novel BDK inhibitor (IC(50) = 3.19 μM). BT2 binds to the same site in BDK as other known allosteric BDK inhibitors, including (S)-α-cholorophenylproprionate ((S)-CPP). BT2 binding to BDK triggers helix movements in the N-terminal domain, resulting in the dissociation of BDK from the BCKDC accompanied by accelerated degradation of the released kinase in vivo. BT2 shows excellent pharmacokinetics (terminal T(1⁄2) = 730 min) and metabolic stability (no degradation in 240 min), which are significantly better than those of (S)-CPP. BT2, its analog 3-chloro-6-fluorobenzo[ b]thiophene-2-carboxylic acid (BT2F), and a prodrug of BT2 (i.e. N-(4-acetamido-1,2,5-oxadiazol-3-yl)-3,6-dichlorobenzo[ b]thiophene-2-carboxamide (BT3)) significantly increase residual BCKDC activity in cultured cells and primary hepatocytes from patients and a mouse model of maple syrup urine disease. Administration of BT2 at 20 mg/kg/day to wild-type mice for 1 week leads to nearly complete dephosphorylation and maximal activation of BCKDC in heart, muscle, kidneys, and liver with reduction in plasma BCAA concentrations. The availability of benzothiophene carboxylate derivatives as stable BDK inhibitors may prove useful for the treatment of metabolic disease caused by elevated BCAA concentrations.
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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.