| Literature DB >> 30623649 |
Dahye Lee1, Haushabhau S Pagire1, Suvarna H Pagire1, Eun Jung Bae1, Mahesh Dighe1, Minhee Kim1, Kyu Myung Lee2, Yoon Kyung Jang2, Ashok Kumar Jaladi2, Kwan-Young Jung2, Eun Kyung Yoo3, Hee Eon Gim3, Seungmi Lee3, Won-Il Choi3, Young-In Chi3, Jin Sook Song2, Myung Ae Bae2, Yong Hyun Jeon3,4, Ga-Hyun Lee5, Kwang-Hyeon Liu5, Taeho Lee5, Sungmi Park3, Jae-Han Jeon3,6, In-Kyu Lee3,6, Jin Hee Ahn1.
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.Entities:
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Year: 2019 PMID： 30623649 DOI： 10.1021/acs.jmedchem.8b01168
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446