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Design, Synthesis, and Evaluation of Novel Imidazo[1,2-a][1,3,5]triazines and Their Derivatives as Focal Adhesion Kinase Inhibitors with Antitumor Activity
- Source :
- Journal of Medicinal Chemistry. 58:237-251
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
Abstract
- A series of triazinic inhibitors of focal adhesion kinase (FAK) have been recently shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. We report herein that we further explored the heterocyclic core of these inhibitors by a fused imidazole ring with the triazine to provide imidazo[1,2-a][1,3,5]triazines. Importantly, these new compounds displayed 10(-7)-10(-8) M IC50 values, and the best inhibitor showed IC50 value of 50 nM against FAK enzymatic activity. Several inhibitors potently inhibited the proliferation of a panel of cancer cell lines expressing high levels of FAK. Apoptosis analysis in U87-MG and HCT-116 cell lines suggested that these compounds delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that these compounds strongly inhibited cell-matrix adhesion, migration, and invasion of U87-MG cells.
- Subjects :
- Models, Molecular
Cell Survival
Antineoplastic Agents
Apoptosis
Focal adhesion
Cell Movement
Cell Line, Tumor
Drug Discovery
Cell Adhesion
Humans
Phosphorylation
Protein Kinase Inhibitors
IC50
chemistry.chemical_classification
Dose-Response Relationship, Drug
Molecular Structure
Triazines
Chemistry
Cell growth
Imidazoles
Adhesion
Cell cycle
HCT116 Cells
Protein Structure, Tertiary
G2 Phase Cell Cycle Checkpoints
Enzyme
Models, Chemical
Biochemistry
Cell culture
Drug Design
Focal Adhesion Protein-Tyrosine Kinases
Molecular Medicine
Protein Binding
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....f68cb91626f98e3f9624bb827a6894cb