Among the four isotypes (PDK1-4), Pyruvate dehydrogenase kinase 4 (PDK4) is mainly and drastically increased in the liver, skeletal muscle, and adipose tissue. Its activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. PDK4-IN-1 hydrochloride, an anthraquinone derivative, is a potent and orally active allosteric PDK4 inhibitor with an IC50 value of 84 nM. In HEK293T human embryonic kidney cells, PDK4-IN-1 hydrochloride (10 μM) successfully inhibited phosphorylation of Ser232, Ser293, and Ser300 of PDHE1α. PDK4-IN-1 hydrochloride showed good bioavailability (64%), long half-life (>7 h), and moderate clearance (CL = 0.69) in rats. Diet-induced obese mice were orally treated with 100 mg of PDK4-IN-1 hydrochloride for 1 week, and it significantly improved glucose tolerance, as quantified by the area under the curve (AUC). Pre-incubation with PDK4-IN-1 dose-dependently inhibited the release of β-hexosaminidase from IgE/antigen-activated BMMCs, showing that the absorbance values are 0.26 ± 0.025, 0.20 ± 0.015, and 0.126 ± 0.032 in IgE/Ag, 10 μM, and 20 μM PDK4-IN-1-treated BMMCs. PDK4-treated mice showed a marked reduction in extravasation by Evans blue solution. Levels of Evans blue exudation was 149.0 ± 16.9, and 49.9 ± 24.1 in vehicle, and 50 mg/kg PDK4-IN-1-treated mice. In addition, CCK-8 assay showed that the treatment of 50 μM compound PDK4-IN-1 hydrochloride significantly impeded the proliferation of human colon cancer cell lines, HCT116 and RKO[1].
作用机制
The predicted PDK4/inhibitor complex displayed an optimal fitting of the compound into the lipoamide binding site[1].
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