Discovery of Novel Pyruvate Dehydrogenase Kinase 4 (PDK4) Inhibitors for Metabolic Diseases and Cancer

Abstract

Decreased activity of pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase (PDK) can cause several metabolic diseases and cancer. PDK inhibits PDC by phosphorylating the serine residues of the E1α subunit of PDC. Hyperactivation of PDK induces dysregulation of the glucose metabolism that can cause hyperglycemia and diabetes. A high level of PDK4 is observed in type 2 diabetes patients. PDK also contributes to cancer metabolism called the “Warburg effect”. Thus, inhibition of PDK is an efficient therapeutic method for diabetes and cancer. PDK has four isozymes. In this study, we focused on PDK4 and its inhibitors. We designed PDK4 inhibitors based on 9H-Xanthen-9-one scaffold. The activity of synthesized compounds toward PDK4 was checked by absorbance of produced NADH. Then, western blot analysis was conducted for the phosphorylated serine level. hERG potassium channel inhibition study and pharmacokinetics were also examined. Overall, 18e showed the best activity for PDK4 compared to reference compound PS10. 18e also showed a good result on a phosphorylation assay. Furthermore, 18e exhibited no inhibition of hERG and a good PK profile.