Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study
| Autor: | Dongmei Zhao, Ruifeng Wang, Xiangxin Zhao, Maosheng Cheng, Hengxian Cui, Chenzhou Hao, Tianxiao Wu, Yixuan Chen, Sijia Yu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Pyridines
Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Focal adhesion Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Tumor Cells Cultured Humans Pyrroles Cytotoxicity Protein Kinase Inhibitors Molecular Biology Cell Proliferation chemistry.chemical_classification Wound Healing Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Kinase Organic Chemistry 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme Docking (molecular) Focal Adhesion Protein-Tyrosine Kinases Drug Screening Assays Antitumor Lead compound Tyrosine kinase Intracellular |
| Zdroj: | Bioorganic Chemistry. 102:104092 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.104092 |
| Popis: | Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect