2. Academic Validation
  3. Reversing the Warburg effect: Discovery of potent pyruvate dehydrogenase kinase inhibitors for inhibiting tumor growth

Reversing the Warburg effect: Discovery of potent pyruvate dehydrogenase kinase inhibitors for inhibiting tumor growth

  • Bioorg Chem. 2025 Dec:167:109224. doi: 10.1016/j.bioorg.2025.109224.
Meiyan Tang 1,  Yiyang Li 2,  Pengju Ye 1,  Yanliu Peng 1,  Yijia Tang 1,  Zhe Wang 3,  Hongxiang Xiao 4,  Li-Li Wang 1,  Xiaoyong Lei 1,  Zhizhong Xie 1,  Xiaoyan Yang 1,  Guotao Tang 5,  Xiangping Deng 6
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 2 The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; The First Affiliated Hospital of Hunan University of Medicine, Huaihua 418099, Hunan, China.
  • 3 The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
  • 4 Hunan Haopifu Pharmaceutical Co., Ltd, Hunan, China.
  • 5 The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: [email protected].
  • 6 The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Hunan Haopifu Pharmaceutical Co., Ltd, Hunan, China. Electronic address: [email protected].
PMID: 41223594 DOI: 10.1016/j.bioorg.2025.109224
Abstract

Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in tumors, driving Cancer progression by promoting the Warburg effect. Consequently, PDK1 inhibition represents a promising Anticancer strategy, though potent low-toxicity inhibitors remain scarce. In this study, 20 new derivatives were designed and synthesized through further structural optimization of the dichloroacetate (DCA) derivatives, and their inhibitory effects on PDK1 and Anticancer activities were systematically evaluated. Compound D16 emerged as the lead candidate, demonstrating potent PDK1 inhibition (53.20 % at 1 μM), significant suppression of Cancer cells proliferation (A549 IC50 = 0.86 μM) and migration. Notably, D16 reverses the Warburg effect, shifting cellular energy metabolism from glycolysis toward Oxidative Phosphorylation, evidenced by increased acetyl-CoA, reduced lactate, elevated ROS, and induced Apoptosis. Importantly, low-dose D16 (20 mg/kg) robustly inhibited tumor growth in vivo without systemic toxicity. These findings establish D16 as a potent PDK1 inhibitor that shifts tumor metabolism, offering a promising therapeutic approach for Cancer treatment.

Keywords

Anticancer; Pyruvate dehydrogenase kinase 1; Warburg effect.

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