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Identification of a new pyruvate kinase M2 isoform ( PKM 2) activator for the treatment of non‐small‐cell lung cancer ( NSCLC )
Author(s) -
Li RunZe,
Fan XingXing,
Shi DanFeng,
Zhu GuoYuan,
Wang YuWei,
Luo LianXiang,
Pan HuDan,
Yao XiaoJun,
Leung Elaine LaiHan,
Liu Liang
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13354
Subject(s) - chemistry , protein kinase b , activator (genetics) , cancer cell , mtt assay , cancer research , kinase , docking (animal) , a549 cell , apoptosis , cancer , biochemistry , biology , receptor , medicine , nursing , genetics
Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore, we aimed to identify new compounds that might act as pyruvate kinase M2 isoform ( PKM 2) activators and to investigate their anti‐cancer efficacy in non‐small‐cell lung cancer ( NSCLC ) cells. The molecular docking method was applied to screen PKM 2 activators from our virtual natural products library. Then, compounds with promising docking scores were examined for cytotoxic effects in a panel of NSCLC cells using the MTT assay. Functional effects and therapeutic mechanisms were investigated by in vitro enzyme assays, western blotting ( WB ), and flow cytometry. Molecular docking showed that 0089‐0022 acts as a potential PKM 2 activator by binding to the kinase pocket. An in vitro enzyme activity assay showed that 0089‐0022 is a direct PKM 2 activator and that it effectively induces apoptosis in A549 and H1975 cells through inhibition of AKT phosphorylation. Our results suggest that 0089‐0022 activates PKM 2 and thus is a promising anti‐cancer therapeutic candidate in NSCLC .