Design, Synthesis, and Biological Evaluation of Covalent Inhibitors of Focal Adhesion Kinase (FAK) against Human Malignant Glioblastoma

被引:34
作者
Li, Bo [1 ]
Li, Yongliang [2 ]
Tomkiewicz-Raulet, Celine [3 ]
Dao, Pascal [4 ]
Lietha, Daniel [5 ]
Yen-Pon, Expedite [1 ]
Du, Zhiyun [2 ]
Coumoul, Xavier [3 ]
Garbay, Christiane [1 ]
Etheve-Quelquejeu, Melanie [1 ]
Chen, Huixiong [1 ]
机构
[1] Univ Paris, UMR8601, CNRS, Chem RNA Nucleosides Peptides & Heterocycles, F-75006 Paris, France
[2] Guangdong Univ Technol, Sch Chem Engn & Light Ind, Guangzhou 510006, Peoples R China
[3] Univ Paris, UMR S 1124, INSERM, Toxicol Pharmacol & Signalisat Cellulaire, F-75006 Paris, France
[4] Univ Cote dAzur, CNRS, Inst Chim Nice, UMR7272, F-06108 Nice, France
[5] CSIC, Biol Res Ctr CIB, Struct & Chem Biol, Cell Signalling & Adhes Grp, Madrid 28040, Spain
基金
中国国家自然科学基金;
关键词
D O I
10.1021/acs.jmedchem.0c01059
中图分类号
R914 [药物化学];
学科分类号
100701 ;
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-kappa B. These data demonstrated that these inhibitors may have the potential to offer a promising new targeted therapy for human glioblastomas.
引用
收藏
页码:12707 / 12724
页数:18
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