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

摘要

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 IC 50 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. Graphical abstract Display Omitted Highlights ? The novel dithiocarbamate substituted naphthoquinone derivatives were designed and synthesized. ? All compounds were evaluated for in?vitro PKM2 inhibitory activity and antiproliferative activity. ? Compound 3k showed more potent PKM2 inhibitory activity than the positive control shikonin. ? Compound 3k exhibited nanomolar antitumor activity toward PKM2 high expression cancer cell lines.