Abstract
Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound 31e exhibited potent antiproliferative activity (IC50 (50% inhibitory concentration) = 0.026 μΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells. A mechanism study demonstrated that 31e induced G1 phase (First growth phase or G indicating gap) arrest, inhibited the phosphorylation of c-Met and its downstream signaling component, Akt (Protein Kinase B), and also inhibited the migration of hepatic carcinoma 97H cells.
Highlights
Cancer is a major disease that seriously threatens human health
The synthesis of target compounds 11a and 11b is summarized in Scheme 1
Aktof treated with compound 31e at a concentration of 10 or 50 nM for 1 h, the phosphorylation level and chemists.Mesenchymal−epithelial transition factor (c-Met) was suppressed in a dose-dependent manner
Summary
Cancer is a major disease that seriously threatens human health. According to statistics from the. Type I inhibitors are generally described as specific for c-Met kinase and more selective than class II inhibitors Reported optimized pyridazinones as Tepotinib being potent and selective c-Met kinase inhibitors [15]. D. Ghate et al described the recent advances of the small molecule c-Metof kinase inhibitors, including including several pyridazinone derivatives, but similar structures our compounds have not. D. Ghate et al described the recent advances of small molecule c-Met kinase inhibitors, several pyridazinone derivatives, but the similar structures of our compounds have not been reported been reported before [16]. Inspired by thetointeresting scaffold of Tepotinib, we decided synthesize new Tepotinib derivatives to find leading compounds with good activity and limited side effects. We reported the synthesis, evaluation, and optimization of new Tepotinib derivatives as anti-tumor agents.
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