Dual targeting of VEGFR-2 and FAK kinases by novel benzimidazole-oxadiazole hybrids: a potential approach in cancer therapy.

In this study, a novel series of benzimidazole-oxadiazole hybrids 8a-x were rationally designed as dual type II VEGFR-2 and FAK inhibitors. The design strategy posits that the benzimidazole accommodates at the interface between the gate area and the hydrophobic back pocket of the inactive conformation of the target kinases where it engages in hydrogen bonding through the fused imidazole ring with the surrounding key amino acids. Through a phenyl spacer, the substituted oxadiazole ring is oriented toward the hinge region of the target kinases engaging in hydrogen bonding with the key hinge region residues. The designed benzimidazole-oxadiazole conjugates 8a-x exhibited a pronounced inhibitory activity on VEGFR-2. Derivatives 8f, 8g, and 8s revealed IC50 values of 3.10, 2.64, and 1.18 µM, respectively on VEGFR-2, while the derivative 8f revealed an IC50 value of 1.56 µM on FAK. On NCI-USA 60 cell lines, the synthesized benzimidazole-oxadiazole conjugates 8a-x revealed moderate to potent growth inhibition with mean GI% values up to 115.28% at 10 µM. Additionally, compounds 8m and 8s were selected for 5-dose assay where they exhibited potent growth inhibitory activity, with GI50 values spanning 1.41-11.4 µM and 1.57-31.6 µM, respectively. Compound 8s induced cell cycle arrest at the G2/M phase in the T47D breast cancer cell line and demonstrated potential to promote apoptosis. Molecular docking and molecular dynamic simulations in VEGFR-2 and FAK binding sites confirmed the proposed binding mode and the stable accommodation of the designed benzimidazole-oxadiazole conjugate 8s within the kinase domain of both targets.