2. Academic Validation
  3. Novel inhibitors targeting the PGK1 metabolic enzyme in glycolysis exhibit effective antitumor activity against kidney renal clear cell carcinoma in vitro and in vivo

Novel inhibitors targeting the PGK1 metabolic enzyme in glycolysis exhibit effective antitumor activity against kidney renal clear cell carcinoma in vitro and in vivo

  • Eur J Med Chem. 2024 Mar 5:267:116209. doi: 10.1016/j.ejmech.2024.116209.
Yu He 1,  Yinheng Luo 2,  Lan Huang 3,  Dan Zhang 4,  Huijin Hou 5,  Yue Liang 6,  Shi Deng 7,  Peng Zhang 8,  Shufang Liang 9
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 2 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 3 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 7 Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 8 Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 9 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: [email protected].
PMID: 38354523 DOI: 10.1016/j.ejmech.2024.116209
Abstract

Our previous research has revealed phosphoglycerate kinase 1 (PGK1) enhances tumorigenesis and sorafenib resistance of kidney renal clear cell carcinoma (KIRC) by regulating glycolysis, so that PGK1 is a promising drug target. Herein we performed structure-based virtual screening and series of Anticancer pharmaceutical experiments in vitro and in vivo to identify novel small-molecule PGK1-targeted compounds. As results, the compounds CHR-6494 and Z57346765 were screened and confirmed to specifically bind to PGK1 and significantly reduced the metabolic Enzyme activity of PGK1 in glycolysis, which inhibited KIRC cell proliferation in a dose-dependent manner. While CHR-6494 showed greater anti-KIRC efficacy and fewer side effects than Z57346765 on nude mouse xenograft model. Mechanistically, CHR-9464 impeded glycolysis by decreasing the metabolic Enzyme activity of PGK1 and suppressed histone H3T3 phosphorylation to inhibit KIRC cell proliferation. Z57346765 induced expression changes of genes related to cell metabolism, DNA replication and cell cycle. Overall, we screened two novel PGK1 inhibitors, CHR-6494 and Z57346765, for the first time and discovered their potent anti-KIRC effects by suppressing PGK1 metabolic Enzyme activity in glycolysis.

Keywords

CHR-6494; Glycolysis; Kidney renal clear cell carcinoma; PGK1 inhibitor; Structure-based virtual screening; Z57346765.

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