Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases.
Dahye LeeHaushabhau S PagireSuvarna H PagireEun Jung BaeMahesh DigheMinhee KimKyu Myung LeeYoon Kyung JangAshok Kumar JaladiKwan-Young JungEun Kyung YooHee Eon GimSeungmi LeeWon-Il ChoiYoung-In ChiJin Sook SongMyung Ae BaeYong Hyun JeonGa-Hyun LeeKwang-Hyeon LiuTaeho LeeSungmi ParkJae-Han JeonIn-Kyu LeeJin Hee AhnPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- molecular docking
- small molecule
- cell proliferation
- mouse model
- insulin resistance
- oxidative stress
- molecular dynamics simulations
- adipose tissue
- ms ms
- cell death
- papillary thyroid
- photodynamic therapy
- endoplasmic reticulum stress
- physical activity
- high fat diet
- high throughput
- squamous cell carcinoma
- cell cycle
- skeletal muscle
- risk assessment
- cell cycle arrest
- climate change
- polycystic ovary syndrome
- smoking cessation
- protein kinase
- replacement therapy