ABSTRACT
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) were identified in approximately 15% of all patients with non-small cell lung cancer (NSCLC). These mutations have been established as an indicator of superior response to gefitinib and erlotinib, small molecule inhibitors of the EGFR kinase domain. Whether these mutations would also render patients more susceptible to treatment with cetuximab (Erbitux), an EGFR-neutralizing antibody, is yet to be determined. In this study, we attempted to evaluate the effect of cetuximab on several NSCLC lines harboring some of the more common EGFR mutations (L858R and delL747-T753insS), as well as the recently identified kinase inhibitor-resistant mutation, T790M. We could show that the kinase activity of the abovementioned EGFR mutants was hindered by cetuximab, as detected by both cell-based phosphorylation and proliferation assays. Interestingly, cetuximab also induced enhanced degradation of the EGFR mutants as compared with the wild-type receptor. Most importantly, cetuximab successfully inhibited the growth of NSCLC lines in xenograft models. These results indicate the promising potential of cetuximab as a regimen for patients with NSCLC bearing these mutations.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation/drug effects , Animals , Antibodies, Monoclonal, Humanized , Apoptosis , Blotting, Western , Cell Line, Tumor , Cetuximab , Dimerization , ErbB Receptors/metabolism , Female , Fluorescent Antibody Technique , Humans , Immunoblotting , Immunoprecipitation , Mice , Mice, Nude , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Ubiquitin/metabolismABSTRACT
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Subject(s)
Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Antineoplastic Agents/pharmacology , Azepines/chemistry , Cell Line, Tumor , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitory Concentration 50 , Neoplasm Proteins/antagonists & inhibitors , Phosphorylation/drug effects , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Subject(s)
Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Animals , Antimitotic Agents/chemistry , Antimitotic Agents/classification , Biopolymers/chemistry , Biopolymers/metabolism , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Protein Conformation/drug effects , Structure-Activity RelationshipABSTRACT
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.
