123rd General Meeting of the KCS

Type Symposium
Area The Cutting Edge of Drug Discovery Chemistry
Room No. Room 304
Time THU 17:20-17:50
Code MEDI-4
Subject Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases
Authors Jin hee Ahn
Department of Chemistry, Gwangju Institute of Science and Technology, Korea
Abstract Glycolysis, the initial stage of glucose metabolism, yields a two ATPs, two NADHs and two molecules of three-carbon compound pyruvate from glucose. Subsequently, pyruvate generated from glycolysis is catalyzed into acetyl-coenzyme A (Acetyl CoA) by pyruvate dehydrogenase complex (PDC). Acetyl CoA enters the tricarboxylic acid cycle and finally produces ATP, which is an energy source for the body. This cascade is coupled to the synthesis of 36 molecules of ATP by oxidative phosphorylation. The enzymatic activity of PDC is inhibited by pyruvate dehydrogenase kinases (PDK1-4) by phosphorylating three serine residues on its E1α subunit ; Ser232, Ser293 and Ser300 with different specificity for each sites. Many previous studies have demonstrated that dysregulation of the PDH/PDK system is implicated in the onset of various diseases such as cancer, metabolic diseases, and inflammation, suggesting that PDKs are a potent therapeutic target for these diseases. Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies and cancer. GM compound showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles and possible metabolites were suggested. GM compound improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in passive cutaneous anaphylaxis (PCA) mouse model. Additionally, GM compound exhibited anti-cancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, GM compound displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development towards PDK 4 inhibitors.
E-mail jhahn@gist.ac.kr