酪氨酸激酶
细胞粘附
激酶
原癌基因酪氨酸蛋白激酶Src
磷酸化
细胞生物学
PTK2
生物化学
作者
Bo Li,Yongliang Li,Céline Tomkiewicz-Raulet,Pascal Dao,Daniel Lietha,Expédite Yen-Pon,Zhiyun Du,Xavier Coumoul,Christiane Garbay,Mélanie Etheve-Quelquejeu,Huixiong Chen
标识
DOI:10.1021/acs.jmedchem.0c01059
摘要
Human malignant glioblastoma (GBM) is a highly invasive and lethal brain tumor. Targeting of integrin downstream signaling mediators in GBM such as focal adhesion kinase (FAK) seems reasonable and recently demonstrated promising results in early clinical studies. Herein, we report the structure-guided development of a series of covalent inhibitors of FAK. These new compounds displayed highly potent inhibitory potency against FAK enzymatic activity with IC50 values in the nanomolar range. Several inhibitors retarded tumor cell growth as assessed by a cell viability assay in multiple human glioblastoma cell lines. They also significantly reduced the rate of U-87 cell migration and delayed the cell cycle progression by stopping cells in the G2/M phase. Furthermore, these inhibitors showed a potent decrease of autophosphorylation of FAK in glioblastoma cells and its downstream effectors Akt and Erk as well as nuclear factor-κB. These data demonstrated that these inhibitors may have the potential to offer a promising new targeted therapy for human glioblastomas.
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