2. Academic Validation
  3. Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases

Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases

  • J Med Chem. 2019 Jan 24;62(2):575-588. doi: 10.1021/acs.jmedchem.8b01168.
Dahye Lee 1,  Haushabhau S Pagire 1,  Suvarna H Pagire 1,  Eun Jung Bae 1,  Mahesh Dighe 1,  Minhee Kim 1,  Kyu Myung Lee 2,  Yoon Kyung Jang 2,  Ashok Kumar Jaladi 2,  Kwan-Young Jung 2,  Eun Kyung Yoo 3,  Hee Eon Gim 3,  Seungmi Lee 3,  Won-Il Choi 3,  Young-In Chi 3,  Jin Sook Song 2,  Myung Ae Bae 2,  Yong Hyun Jeon 3 4,  Ga-Hyun Lee 5,  Kwang-Hyeon Liu 5,  Taeho Lee 5,  Sungmi Park 3,  Jae-Han Jeon 3 6,  In-Kyu Lee 3 6,  Jin Hee Ahn 1
Affiliations

Affiliations

  • 1 Department of Chemistry , Gwangju Institute of Science and Technology , Gwangju 61005 , Republic of Korea.
  • 2 Bio & Drug Discovery Division , Korea Research Institute of Chemical Technology , Daejeon 34114 , Republic of Korea.
  • 3 Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease , Kyungpook National University Hospital , Daegu 41404 , Republic of Korea.
  • 4 Laboratory Animal Center , Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061 , Republic of Korea.
  • 5 College of Pharmacy, Research Institute of Pharmaceutical Sciences , Kyungpook National University , Daegu 41566 , Republic of Korea.
  • 6 Department of Internal Medicine, School of Medicine , Kyungpook National University, Kyungpook National University Hospital , Daegu 41944 , Republic of Korea.
PMID: 30623649 DOI: 10.1021/acs.jmedchem.8b01168
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.

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