期刊
PHARMACOLOGICAL RESEARCH
卷 164, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2020.105367
关键词
Hexokinase 2; Cancer metabolism; Glycolysis; Cancer therapeutics
资金
- National Natural Science Foundation of China (NSFC) [81473254, 81903863, 81773637, U1803122]
- China Postdoctoral Science Foundation [2019M652661]
- Fundamental Research Fund for the Central Universities [2017KFYXJJ151]
- Liaoning Revitalization Talents Program [XLYC1807182]
- Liaoning Province Natural Science Foundation [2019-MS-299]
The novel selective HK2 inhibitor BNBZ was reported to directly bind to HK2, induce cancer cell apoptosis, and inhibit glycolysis of cancer cells. BNBZ significantly inhibited cancer cell proliferation in vitro and in vivo by targeting HK2 with high potency and low toxicity.
Accelerated glucose metabolism is a common feature of cancer cells. Hexokinase 2 (HK2) as the rate-limiting enzyme catalyzes the first step of glucose metabolism. It is overexpressed in most of the human cancers and has been a promising target for cancer therapy. Here, we report a novel selective HK2 inhibitor Benitrobenrazide (BNBZ), with nanomolar inhibitory potency. In vitro, BNBZ directly binds to HK2, induces apoptosis, and inhibits proliferation of HK2-overexpressed cancer cells. BNBZ also significantly inhibits the glycolysis of SW1990 cells by targeting HK2. The knockdown or knockout of HK2 expression in SW1990 cells can reduce their sensitivity to BNBZ. Additionally, oral administration of BNBZ can effectively inhibit tumor growth in SW1990 and SW480 xenograft models. In general, BNBZ significantly inhibited glycolysis and cancer cell proliferation in vitro and in vivo by directly targeting HK2 with high potency and low toxicity, and can be developed as a novel HK2 small-molecule candidate drug for future cancer therapeutics.
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