FAK (focal adhesion kinase), a cytoplasmic non-receptor protein-tyrosine kinase, is associated with tumor progression through its modulation of various cellular processes including growth, survival, and migration. PND-1186 is reversible FAK inhibitor with IC50 value of 1.5 nM (measured by purified FAK kinase activity). It had IC50 value of about 100 nM for inhibition of p-FAK-Y397 in breast carcinoma cells. Exposure to 1 μM PND-1186 for 22 h restrains 4T1 breast carcinoma motility with only 40% closure, but no cell detachment or death observed, in wound healing assays. Low-concentration treatment with PND-1186 at 0.1-1 μM for 24-72 h caused dose- and time-dependent increased apoptosis of 4T1 cells cultured in suspension, but not under adherent condition. Consistent with this, PND-1186 could reduce the spheroid size of 3D-cultured 4T1 cells for 3 fold at concentration of 0.1 μM for 72 h with maximal effects achieved at 0.2 μM, which may due to the inhibition of tyrosine phosphorylation of both FAK and p130Cas under spheroid growth conditions but not 2D culture. Oral administration of PND-1186 at 100 mg/kg, BID, for 5 days inhibited 4T1 subcutaneous tumor growth in mice through induction of apoptosis[1].
搜索
