2. Academic Validation
  3. Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase

Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase

  • Eur J Med Chem. 2017 Sep 29;138:343-352. doi: 10.1016/j.ejmech.2017.06.064.
Xianling Ning 1,  Hailong Qi 2,  Ridong Li 1,  Yunqiao Li 3,  Yan Jin 3,  Michael A McNutt 4,  Junyi Liu 5,  Yuxin Yin 6
Affiliations

Affiliations

  • 1 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China.
  • 3 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 4 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
  • 6 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. Electronic address: yinyuxin@hsc.pku.edu.cn.
PMID: 28688274 DOI: 10.1016/j.ejmech.2017.06.064
Abstract

Pyruvate Kinase M2 (PKM2) is a rate-limiting Enzyme of the glycolytic pathway which is highly expressed in Cancer cells. Cancer cells rely heavily on PKM2 for anabolic and energy requirements, and specific targeting of PKM2 therefore has potential as strategy for Cancer therapy. Here, we report the synthesis and biologic evaluation of novel naphthoquinone derivatives as selective small molecule inhibitors of PKM2. Some target compounds, such as compound 3k, displayed more potent PKM2 inhibitory activity than the reported optimal PKM2 inhibitor shikonin. The well performing compound 3k also showed nanomolar antiproliferative activity toward a series of Cancer cell lines with high expression of PKM2 including HCT116, Hela and H1299 with IC50 values ranging from 0.18 to 1.56 μM. Moreover, compound 3k exhibited more cytotoxicity on Cancer cells than normal cells. The identification of novel potent small molecule inhibitors of PKM2 not only offers candidate compounds for Cancer therapy, but also provides a tool with which to evaluate the function of PKM2 in depth.

Keywords

Antiproliferative activity; Naphthoquinone derivatives; PKM2 inhibitor; Pyruvate kinase M2.

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