Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents
| Autor: | Ruifeng Wang, Sijia Yu, Dongmei Zhao, Tianxiao Wu, Maosheng Cheng, Yixuan Chen, Chenzhou Hao, Bowen Yang, Xiangxin Zhao, Jing Guo |
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| Rok vydání: | 2019 |
| Předmět: |
Pyrimidine
Cell Survival Antineoplastic Agents Apoptosis 01 natural sciences Cell Line Focal adhesion 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Cytochrome P-450 Enzyme System Drug Stability Drug Discovery Structure–activity relationship Animals Humans Cytotoxicity Protein Kinase Inhibitors 030304 developmental biology Cell Proliferation Pharmacology chemistry.chemical_classification 0303 health sciences Molecular Structure 010405 organic chemistry Chemistry Kinase Organic Chemistry General Medicine 0104 chemical sciences Rats Molecular Docking Simulation Enzyme Pyrimidines Biochemistry Docking (molecular) Focal Adhesion Protein-Tyrosine Kinases Drug Screening Assays Antitumor Protein Binding |
| Zdroj: | European journal of medicinal chemistry. 183 |
| ISSN: | 1768-3254 |
| Popis: | A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10−8–10−9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 μM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors. |
| Databáze: | OpenAIRE |
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