Abstract
Backgroundc-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.MethodsCompounds 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.ResultsKRC-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 xenograft assay showed KRC-00715 reduced the tumor size significantly.ConclusionsOur in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2058-y) contains supplementary material, which is available to authorized users.
Highlights
Oncogene addiction, which was first proposed by Dr Bernard Weinstein, offers a rationale for the recent targeted therapy in cancer biology [1]
Identification of KRC-00509 and KRC-00715 as potent inhibitors against c-Met kinase Cui et al suggested that PF-04217903, which has triazolopyrazine scaffold, is effective for c-Met inhibition [30]
The enzymatic activities were determined by Homogeneous time resolved fluorescence (HTRF) kinase assay using recombinant kinase domain of c-Met
Summary
Oncogene addiction, which was first proposed by Dr Bernard Weinstein, offers a rationale for the recent targeted therapy in cancer biology [1]. In view of oncogene addiction, RTKs have been highlighted as promising therapeutic targets against cancer for their links with various malignancies [2]. The c-MET receptor tyrosine kinase forms a heterodimer and consists of an extracellular α-chain and a membrane-spanning β-chain [3, 4]. Phosphorylated Y1349 and Y1356 serve as docking sites for the intracellular adapters which transmit signals downstream [6, 7]. Both c-Met and HGF are required for normal mammalian development [8]. C-Met activation by HGF is likely to be involved in epithelial-mesenchymal transition
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