Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC50 range; 2.88 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC50 value of 18.10 nM better than the reference GSK-2256098 (IC50 = 22.14 nM). The preliminary mechanism investigation by Western blot analysis showed that both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt, JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers.
