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  3. Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy

Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy

  • J Med Chem. 2023 Jul 13;66(13):8464-8483. doi: 10.1021/acs.jmedchem.3c00118.
Ruoxi Sang 1 2,  Renming Fan 1 2,  Aohua Deng 1 2,  Jiakui Gou 3,  Ruizhuo Lin 1 2,  Ting Zhao 3,  Yongrui Hai 1 2,  Junke Song 4,  Yang Liu 3,  Bing Qi 5,  Guanhua Du 4,  Maosheng Cheng 3,  Gaofei Wei 1 2
Affiliations

Affiliations

  • 1 Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China.
  • 2 Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4 Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 5 Institute of Oncology, The Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710038, China.
PMID: 37376788 DOI: 10.1021/acs.jmedchem.3c00118
Abstract

Hexokinase 2 (HK2) is the principal rate-limiting Enzyme in the aerobic glycolysis pathway and determines the quantity of glucose entering glycolysis. However, the current HK2 inhibitors have poor activity, so we used proteolysis-targeting chimera (PROTAC) technology to design and synthesize novel HK2 degraders. Among them, C-02 has the best activity to degrade HK2 protein and inhibit breast Cancer cells. It is demonstrated that C-02 could block glycolysis, cause mitochondrial damage, and then induce GSDME-dependent Pyroptosis. Furthermore, Pyroptosis induces cell immunogenic death (ICD) and activates antitumor immunity, thus improving antitumor immunotherapy in vitro and in vivo. These findings show that the degradation of HK2 can effectively inhibit the aerobic metabolism of breast Cancer cells, thereby inhibiting their malignant proliferation and reversing the immunosuppressive microenvironment.

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