2. Academic Validation
  3. A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction

A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction

  • Cells. 2023 Dec 30;13(1):87. doi: 10.3390/cells13010087.
Kenichi Aizawa 1 2 3,  Akari Ikeda 4,  Shota Tomida 1,  Koki Hino 1,  Yuuki Sugita 4,  Tomoyasu Hirose 4,  Toshiaki Sunazuka 4,  Hiroshi Kido 5,  Shigeyuki Yokoyama 6,  Ryozo Nagai 7
Affiliations

Affiliations

  • 1 Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Japan.
  • 2 Clinical Pharmacology Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan.
  • 3 Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan.
  • 4 Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo 108-8641, Japan.
  • 5 Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
  • 6 RIKEN Cluster for Science, Technology and Innovation Hub, Yokohama 230-0045, Japan.
  • 7 Jichi Medical University, Shimotsuke 329-0498, Japan.
PMID: 38201291 DOI: 10.3390/cells13010087
Abstract

Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed. Evidence indicating that inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may be cardioprotective has been accumulating. Thus, we focused on vitamin K3 and used its framework as a new PDK4 inhibitor skeleton to synthesize new PDK4 inhibitors that show higher activity than the existing PDK4 inhibitor, dichloroacetic acid, and tested their cardioprotective effects on a mouse heart failure model. Among these inhibitors, PDK4 inhibitor 8 improved EF the most, even though it did not reverse cardiac fibrosis or wall thickness. This novel, potent PDK4 inhibitor may improve EF of failing hearts by regulating bioenergetics via activation of the tricarboxylic acid cycle.

Keywords

1,4-naphthoquinone; PDK4 inhibitor; TCA cycle; heart failure; quinol monooxygenase; vitamin K3.

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