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Updated: Mar 8, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase

Shih-Chia Tso, Mingliang Lou1,2, Cheng-Yang Wu

  • 1Chemistry Center, National Institute of Biological Science , Beijing 102206, China.

Journal of Medicinal Chemistry
|January 14, 2017
PubMed

Insights

A new drug candidate, compound 17, effectively inhibits pyruvate dehydrogenase kinases (PDKs) in the liver. This leads to improved glucose control and reduced fat accumulation in obese mice, offering a potential treatment for type 2 diabetes.

Area of Science:

  • Biochemistry
  • Metabolic Diseases
  • Drug Discovery

Background:

  • Pyruvate dehydrogenase kinases (PDK1-4) regulate the pyruvate dehydrogenase complex (PDC) and are implicated in metabolic disorders like obesity and diabetes.
  • Previous research identified pan-PDK inhibitors PS8 and PS10 targeting the ATP-binding pocket.

Purpose of the Study:

  • To develop a new generation of PDK inhibitors by modifying the scaffold of PS8 and PS10.
  • To evaluate the efficacy of the lead inhibitor, compound 17, in preclinical models of obesity and type 2 diabetes.

Main Methods:

  • Structure-based drug design was used to extend the inhibitor scaffold towards the PDK2 ATP-binding pocket entrance.
  • In vitro biochemical assays determined the IC50 of compound 17 against PDK2.
  • X-ray crystallography elucidated the binding mode of compound 17.
  • Diet-induced obese mice were treated with compound 17 to assess liver-specific PDC activity, glucose tolerance, and hepatic steatosis.

Main Results:

  • Compound 17 demonstrated significantly improved potency (58 nM IC50) compared to PS10 (456 nM).
  • The crystal structure revealed additional interactions of compound 17 with PDK2 via its asparagine moiety.
  • In vivo studies showed liver-specific increases in PDC activity, enhanced glucose tolerance, and reduced hepatic steatosis in obese mice treated with compound 17.

Conclusions:

  • Compound 17 represents a potent, next-generation PDK inhibitor with a promising therapeutic profile.
  • Targeting liver PDKs with compound 17 offers a potential strategy for managing obesity and type 2 diabetes.

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