Discovery of potent Type-II GSK-3β/VEGFR2 inhibitors with promising potential against tongue squamous cell carcinoma.

Kinases have proven to be valuable targets in anti-cancer drug discovery. In this study, we hybridized essential pharmacophores from AZD2858 and sorafenib and conducted structure-activity relationship studies, leading to the identification of a type II kinase inhibitor, compound 9, which potently inhibits GSK-3β and VEGFR2 with IC50 values in the nanomolar range. Western blot analysis revealed that compound 9 suppressed the phosphorylation of VEGFR2, AKT, MEK, and ERK in a dose-dependent manner. In cellular assays, compound 9 effectively inhibited CAL27 cell migration in a wound healing assay and tube formation of HUVECs, while exhibiting minimal or no antiproliferative effects on various cell lines, including MDA-MB-231, MDA-MB-468, A549, CAL27, and HUVEC cells. Moreover, compound 9 demonstrated significant antitumor efficacy in a CAL27 xenograft mouse model, showing promising potential for further development as a therapeutic agent for tongue squamous cell carcinoma.