Novel c-Met inhibitor suppresses the growth of c-Met-addicted gastric cancer cells

BMC Cancer
Chi Hoon ParkSang-Un Choi

Abstract

c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo. Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo. KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograf...Continue Reading

References

Nov 30, 1992·Biochemical and Biophysical Research Communications·H KuniyasuE Tahara
May 11, 1989·Nature·S GiordanoP M Comoglio
Sep 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·M ParkG Vande Woude
Jan 7, 1994·Science·I TsarfatyG F Vande Woude
Jan 16, 1998·Virchows Archiv : an International Journal of Pathology·H TsujimotoT Hattori
Oct 28, 1998·Trends in Cell Biology·C Birchmeier, E Gherardi
May 18, 2001·Nature·P Blume-Jensen, T Hunter
Dec 1, 2001·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Roger AbounaderJohn Laterra
Jul 6, 2002·Science·I Bernard Weinstein
Jan 10, 2003·Journal of Cellular Biochemistry·Yu-Wen Zhang, George F Vande Woude
Dec 20, 2003·Nature Reviews. Molecular Cell Biology·Carmen BirchmeierGeorge F Vande Woude
May 13, 2005·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D CunninghamUNKNOWN ESMO Guidelines Task Force
Jun 14, 2005·Trends in Molecular Medicine·Simona CorsoSilvia Giordano
Feb 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·Gromoslaw A SmolenDaniel A Haber
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ultan McDermottJeffrey Settleman
Mar 25, 2010·Biochemical and Biophysical Research Communications·Yoshinari AsaokaKazuhiko Koike
Sep 16, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiangdong LiuPeggy A Scherle
Jun 20, 2012·Journal of Hematology & Oncology·Lian LiuJin Li
Jun 14, 2014·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Matthew G Oser, Pasi A Jänne
Jun 25, 2014·OncoTargets and Therapy·Rahul A ParikhLeonard J Appleman
Oct 1, 2014·Current Treatment Options in Oncology·Joanna Goździk-SpychalskaRodryg Ramlau
Jun 7, 2015·Cancer Letters·Luigi MaranoAlberto Patriti
Aug 14, 2015·PloS One·Toshiyuki IshiiMakoto Kaneda

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Citations

Aug 30, 2018·International Journal of Cancer. Journal International Du Cancer·Keyu LiXubao Liu
Dec 7, 2018·Expert Opinion on Drug Discovery·Zhi-Gang SunHai-Liang Zhu
Jul 26, 2018·Journal of Biomolecular Structure & Dynamics·Pavithra K BalasubramanianSeung Joo Cho
Oct 26, 2018·International Journal of Molecular Sciences·Heydi Noriega-Guerra, Vanessa Morais Freitas
Jul 21, 2020·Journal of Cellular and Molecular Medicine·Evangelos KoustasAthanasios G Papavassiliou
Sep 19, 2019·Current Topics in Medicinal Chemistry·Peng-Cheng LvZhong-Chang Wang
Aug 4, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Magda BahcallPasi A Jänne
Oct 30, 2020·Journal of Experimental Pharmacology·Haidar El DarsaOmar Abdel-Rahman
Aug 17, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Abdur RaufEman Elsharkawy

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Methods Mentioned

BETA
xenograft

Software Mentioned

GraphPad Prism
imageJ
Image Lab

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