Journal of medicinal chemistry · 2019
Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases.
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Lee Dahye, Pagire Haushabhau S, Pagire Suvarna H, Bae Eun Jung, Dighe Mahesh, Kim Minhee, Lee Kyu Myung, Jang Yoon Kyung, Jaladi Ashok Kumar, Jung Kwan-Young, Yoo Eun Kyung, Gim Hee Eon, Lee Seungmi, Choi Won-Il, Chi Young-In, Song Jin Sook, Bae Myung Ae, Jeon Yong Hyun, Lee Ga-Hyun, Liu Kwang-Hyeon, Lee Taeho, Park Sungmi, Jeon Jae-Han, Lee In-Kyu, Ahn Jin Hee
Аннотация
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.