Abstract
Targeting c-Met is a clinical trend for the precise treatment of HCC, but the potential issue of acquired drug resistance cannot be ignored. Targeted protein degradation technology has demonstrated promising prospects in disease treatment and overcoming drug resistance due to its special mechanism of action. In this study, we designed and synthesized two series of novel c-Met degraders and conducted a systematic biological evaluation of the optimal compound H11. H11 exhibited good c-Met degradation activity and anti-HCC activity. Importantly, H11 also demonstrated more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H cell lines than did tepotinib. In summary, H11 displayed potent anti-HCC activity as a degrader and may overcome resistance to type Ib inhibitors, making it a new therapeutic strategy for HCC with MET alterations.
MeSH terms
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Carcinoma, Hepatocellular* / drug therapy
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Carcinoma, Hepatocellular* / metabolism
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Carcinoma, Hepatocellular* / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Discovery
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Drug Screening Assays, Antitumor
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Humans
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Liver Neoplasms* / drug therapy
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Liver Neoplasms* / metabolism
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Liver Neoplasms* / pathology
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Mice
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-met* / antagonists & inhibitors
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Proto-Oncogene Proteins c-met* / metabolism
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Structure-Activity Relationship
Substances
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Proto-Oncogene Proteins c-met
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Antineoplastic Agents
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MET protein, human
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Protein Kinase Inhibitors