FAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of
targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in
which the kinase has been implicated in promoting metastases. Consequently, designing and developing
potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as
a promising tool in our armamentarium for treating diverse cancers. This review comprehensively
summarizes the different classes of synthetically derived compounds that have been reported as potent
FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed
to slow down the emergence of drug resistance is discussed.

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and
focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of
both HDAC2 (IC50 ¼ 0.09e1.40 mM) and FAK (IC50 ¼ 12.59e36.11 nM); 6a revealed the highest activity
with IC50 values of 0.09 mM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to
reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and
Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M
phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is
observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK
inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized
by molecular docking. Taken together, these findings highlight the potential of 6a as a promising
dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.