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.