2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Covalent Inhibitors of Focal Adhesion Kinase (FAK) against Human Malignant Glioblastoma

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

  • J Med Chem. 2020 Nov 12;63(21):12707-12724. doi: 10.1021/acs.jmedchem.0c01059.
Bo Li 1,  Yongliang Li 2,  Céline Tomkiewicz-Raulet 3,  Pascal Dao 4,  Daniel Lietha 5,  Expédite Yen-Pon 1,  Zhiyun Du 2,  Xavier Coumoul 3,  Christiane Garbay 1,  Mélanie Etheve-Quelquejeu 1,  Huixiong Chen 1
Affiliations

Affiliations

  • 1 Chemistry of RNA, Nucleosides, Peptides and Heterocycles, CNRS UMR8601, Université de Paris, 45 rue des Saints-Pères, 75006 Paris, France.
  • 2 School of Chemical Engineering and Light Industry, Guangdong University of Technology, No. 100 Waihuan Xi Road, Education Mega Center, Guangzhou 510006, China.
  • 3 Toxicologie, Pharmacologie et Signalisation Cellulaire, INSERM, UMR S 1124, Université de Paris, 45 rue des Saints-Pères, 75006 Paris, France.
  • 4 Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France.
  • 5 Cell Signalling and Adhesion Group, Structural and Chemical Biology, Biological Research Center (CIB), Spanish National Research Council (CSIC), Calle Ramiro de Maeztu, Madrid 28040, Spain.
PMID: 33119295 DOI: 10.1021/acs.jmedchem.0c01059
Abstract

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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