Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors
| Autor: | Alessia Calgani, Silvia Schenone, Adriano Angelucci, Anna Lucia Fallacara, Roberto Artusi, Laura Mennuni, Maurizio Botta, Cinzia Maria Francini |
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| Rok vydání: | 2015 |
| Předmět: |
aminoimidazoles
aminothiazoles antitumor agents inhibitors Src kinase Molecular Sequence Data Biology Crystallography X-Ray Biochemistry chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship FYN Aminothiazole LYN Cell Line Tumor Drug Discovery medicine Humans Src family kinase Amino Acid Sequence General Pharmacology Toxicology and Pharmaceutics Protein Kinase Inhibitors Pharmacology Binding Sites Kinase Organic Chemistry Imidazoles Hydrogen Bonding Protein Structure Tertiary Dasatinib Molecular Docking Simulation Thiazoles src-Family Kinases chemistry Molecular Medicine Thermodynamics Tyrosine kinase Sequence Alignment Proto-oncogene tyrosine-protein kinase Src medicine.drug Protein Binding |
| Zdroj: | ChemMedChem. 10(12) |
| ISSN: | 1860-7187 |
| Popis: | Src family kinases (SFKs) are a family of non-receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c-Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4-aminoimidazole and 2-aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2-aminothiazole analogues of dasatinib and 4-aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90-480 nm. A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH-SY5Y and K562 cell lines. Compound 3 b [2-(4-{2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)ethanol] was found to be the most active inhibitor. |
| Databáze: | OpenAIRE |
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