Faculty Collaboration Database

Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases. J Med Chem 2019 Jan 24;62(2):575-588

Date

01/10/2019

Pubmed ID

30623649

DOI

10.1021/acs.jmedchem.8b01168

Scopus ID

2-s2.0-85060048488 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC₅₀ value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.

Author List

Lee D, Pagire HS, Pagire SH, Bae EJ, Dighe M, Kim M, Lee KM, Jang YK, Jaladi AK, Jung KY, Yoo EK, Gim HE, Lee S, Choi WI, Chi YI, Song JS, Bae MA, Jeon YH, Lee GH, Liu KH, Lee T, Park S, Jeon JH, Lee IK, Ahn JH

Author

Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Animals
Anthraquinones
Binding Sites
Cell Line
Half-Life
Humans
Hypoglycemic Agents
Male
Metabolic Diseases
Mice
Mice, Inbred C57BL
Mice, Obese
Microsomes, Liver
Molecular Docking Simulation
Obesity
Protein Kinase Inhibitors
Protein Kinases
Rats
Structure-Activity Relationship