Chapter 15 - Protein kinase inhibitors from discovery to therapeutics

Abstract

Pyruvate dehydrogenase complex (PDC) is the trimeric enzyme complex that converts pyruvate formed from glycolysis to acetyl CoA that is further directed toward the tricarboxylic acid cycle (TCA). The activity of PDC is regulated by pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase by activation and inhibition of PDC respectively. As PDC plays an important role in cellular metabolism, therefore, its regulation is of utmost importance. The imbalance in the regulation of mitochondrial PDC is the hallmark of various metabolic disorders including obesity, diabetes, cancers, neurodegenerative disorders, etc. Phosphorylation of PDC at E1⍺ of pyruvate dehydrogenase subunit by PDK isomers (PDK1–4) deactivates PDC. The PDKs are inhibited by PDK inhibitors that are emerging as a treatment option for various disorders. This book chapter gives an overview of the structure and isomers of PDK, elaborating the role of PDK in various metabolic disorders followed by the efficacy studies of PDK inhibitors.