Design, synthesis, and evaluation of 4-(aminomethyl)-2-(phenylamino)pyridine derivatives as novel lysyl oxidase-like 2 inhibitors against metastatic melanoma.

Despite extensive validation of lysyl oxidase-like 2 (LOXL2) as a therapeutic target in metastatic cancer, there have been few therapeutic applications of corresponding inhibitors until now. Herein, we reported the design, synthesis, and biological evaluation of two series of 4-(aminomethyl)-2-(phenylamino)pyridine derivatives (7a-7u and 10a-10u) as novel LOXL2 inhibitors for metastatic melanoma intervention. Structure-based optimization of 2-substituted pyridine-4-ylmethanamine scaffold led to the identification of 10q, exhibiting notable LOXL2 inhibitory activity with IC50 value of 79.38 nM, superior to the lead compound. In invasive melanoma cells, 10q dose-dependently inhibited proliferation, invasion, migration, and cell-matrix adhesion as well as attenuating focal adhesions (FAs) and stress fibers (SFs) formation. Further mechanism studies revealed that 10q treatment disrupted LOXL2-mediated signaling cascades, as evidenced by decreased phosphorylation of FAK, PI3K, AKT, and mTOR, concomitant with downregulation of Snail 1 and upregulation of the epithelial marker E-cadherin. Collectively, these results indicated that 10q is a novel LOXL2 inhibitor with potent anti-metastasis activity, highlighting its potential as a promising candidate for the intervention of metastatic melanoma.