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

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.