Endocrine Abstracts (2019) 63 P533 | DOI: 10.1530/endoabs.63.P533

A novel oral pyruvate dehydrogenase kinase 4 inhibitor ameliorates various spectrum of metabolic diseases in mice

Jae-Han Jeon1, In-Kyu Lee1, Yeon-Kyung Choi1, Keun-Gyu Park1, Na-Young Kim1, Sung Don Park1, Jin Hee Ahn2 & Min-Ji Kim1

1Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. We report here a new series of allosteric PDK4 inhibitor modified from hit anthraquinone. A novel PDK4 inhibitor, namely compound 8c, improved glucose tolerance in diet-induced obese mice. PDH activity in muscle and liver was enhance d by compound 8c treatment. Given the importance of PDK4 in immune cells including mast cells, we studied the effect of compound 8c in a passive cutaneous anaphylaxis mouse model. Compound 8c successfully improved allergic reactions as evidenced by decreased Evans Blue extravasation in ears. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis in colon cancer cell lines. PDK4 inhibitors could be widely applicable in a various spectrum of metabolic diseases including diabetes, allergies and obesity-related cancers.

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