Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase

Shih Chia Tso, Wen Jun Gui, Cheng Yang Wu, Jacinta L. Chuang, Xiangbing Qi, Kristen J. Skvorak, Kenneth Dorko, Amy L. Wallace, Lorraine K. Morlock, Brendan H. Lee, Susan M. Hutson, Stephen C. Strom, Noelle S. Williams, Uttam K. Tambar, R. Max Wynn, David T. Chuang

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22 Scopus citations

Abstract

The mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC) is negatively regulated by reversible phosphorylation.BCKDCkinase (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 (IC50 = 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 T1/2 = 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 residualBCKDCactivity 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 plasmaBCAAconcentrations. The availability of benzothiophene carboxylate derivatives as stable BDK inhibitors may prove useful for the treatment of metabolic disease caused by elevated BCAA concentrations.

Original languageEnglish (US)
Pages (from-to)20583-20593
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number30
DOIs
StatePublished - Jul 25 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tso, S. C., Gui, W. J., Wu, C. Y., Chuang, J. L., Qi, X., Skvorak, K. J., Dorko, K., Wallace, A. L., Morlock, L. K., Lee, B. H., Hutson, S. M., Strom, S. C., Williams, N. S., Tambar, U. K., Wynn, R. M., & Chuang, D. T. (2014). Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase. Journal of Biological Chemistry, 289(30), 20583-20593. https://doi.org/10.1074/jbc.M114.569251