Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton
Small molecule inhibitors from the focal adhesion kinase are considered as promising tools within our armamentarium for the treatment of cancer. Here, we identified four 1,2,4-triazole derivatives that hinder FAK kinase considerably and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, by which 3c and 3d were probably the most potent (IC50 range 2.88 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC50 worth of 18.10 nM much better than the reference GSK-2256098 (IC50 = 22.14 nM). The preliminary mechanism analysis by Western blot analysis demonstrated that both 3c and 3d repressed FAK phosphorylation similar to GSK-2256098 in HepG2 cells. Because of FAK inhibition, 3c and 3d inhibited the professional-survival pathways by reducing the phosphorylation amounts of PI3K, Akt, JNK, and STAT3 proteins. This effect brought to apoptosis induction and cell cycle arrest. Taken together,GSK2256098 these results indicate that 3d could help as a powerful preclinical candidate to treat cancers.