ABSTRACT
Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC50 value of 3.5 µM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC50 values of 0.63 and 0.32 µM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC50 values of 5.6 and 9.3 µM. Structure-activity relationships have been studied and binding mode of this chemical class has been proposed.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Benzimidazoles/chemistry , Humans , Protein Kinase Inhibitors/chemistryABSTRACT
Fibroblast grow factor receptor 1 (FGFR1) is an important anti-cancer target that plays crucial role in oncogenesis and oncogenic angiogenesis. The structure-activity relationship (SAR) of N-phenylthieno[2,3-d]pyrimidin-4-amines was investigated. Binding of active compounds with FGFR1 kinase was analyzed by molecular modeling studies. Selected active thieno[2,3-d]pyrimidines were tested for selectivity and antiproliferative activity. The most active compounds, 3-({6-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol and 3-({5-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol have IC50 0.16 and 0.18 µM, respectively. The results presented here may help to identify new thienopyrimidines with optimized cell growth inhibitory activity which may be further used as anticancer agents.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
Growth and morphological properties of a novel mouse cell line G1 have been investigated. It has been shown that cells of this cell line possess the ability of spontaneous transformation in vitro: the cells have unlimited growth in culture, grow in medium with a low serum content and form multilayer colonies on a cell monolayer and cell colonies inside agar. Using micronucleus test it has been revealed that cells of the G1 cell line possess different forms of aberrant mitosis. The results indicate the neoplastic G1 cell transformation with aberrant mitosis.
