Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases.

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.

• Authors: Dahye Lee, Haushabhau S Pagire, Suvarna H Pagire, Eun Jung Bae, Mahesh Dighe, Minhee Kim, Kyu Myung Lee, Yoon Kyung Jang, Ashok Kumar Jaladi, Kwan-Young Jung, Eun Kyung Yoo, Hee Eon Gim, Seungmi Lee, Won-Il Choi, Young-In Chi, Jin Sook Song, Myung Ae Bae, Yong Hyun Jeon, Ga-Hyun Lee, Kwang-Hyeon Liu, Taeho Lee, Sungmi Park, Jae-Han Jeon, In-Kyu Lee, Jin Hee Ahn
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 2 Pg. 575-588 (01 24 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30623649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthraquinones
• Hypoglycemic Agents
• Protein Kinase Inhibitors
• Protein Kinases
• pyruvate dehydrogenase kinase 4

Topics

• Administration, Oral
• Animals
• Anthraquinones (chemistry, metabolism, therapeutic use)
• Binding Sites
• Cell Line
• Half-Life
• Humans
• Hypoglycemic Agents (chemistry, metabolism, therapeutic use)
• Male
• Metabolic Diseases (drug therapy, pathology, veterinary)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Microsomes, Liver (metabolism)
• Molecular Docking Simulation
• Obesity (drug therapy, pathology)
• Protein Kinase Inhibitors (chemistry, metabolism, therapeutic use)
• Protein Kinases (chemistry, metabolism)
• Rats
• Structure-Activity Relationship