title: New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds.
abstract: Pyruvate kinase M2 (PKM2) is a key protein responsible for cancer's Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Ridong
authors.initials: R
authors.lastname: Li
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xianling
authors.initials: X
authors.lastname: Ning
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Zemei
authors.initials: Z
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: lirt@bjmu.edu.cn.
authors.forename: Runtao
authors.initials: R
authors.lastname: Li
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: yinyuxin@hsc.pku.edu.cn.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004952:Esters; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D020033:Protein Isoforms; D013859:Thiocarbamates; D011770:Pyruvate Kinase
keywords: Anti-proliferation; Dithiocarbamic acid ester; Docking; Pyruvate kinase M2; Structure–activity relationship