Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-03, Vol.24 (6), p.1173
• Main Authors: Zhang, Niu-Niu, An, Bai-Jiao, Zhou, Yan, Li, Xing-Shu, Yan, Ming
• Format: Article
• Language: English
• Subjects: 97H cells; Acids; AKT protein; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative agents; Antiproliferatives; Binding sites; c-Met inhibitor; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; G1 phase; Gene amplification; Hepatocytes; Humans; Kinases; Liver cancer; low toxicity; Medical prognosis; Mesenchyme; Nitrogen; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24061173

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 exhibited potent antiproliferative activity (IC (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 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.