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.
18 - 21 May 2019
European Society of Endocrinology