From Virtual Screening to Cell Phenotype: 4-Thiazolidone Scaffolds Targeting LOXL2 in Breast Cancer.

Lysyl Oxidases (LOXs) catalyse elastin and collagen cross-linking in the extracellular matrix and have been implicated in cancer cell progression and metastases, particularly in breast cancer. In this study, we sought small-molecule inhibitors of LOXL2 using a library of 4-thiazolidones supported by molecular docking. Five candidates were prioritised, with Les 5740 displaying the highest LOXL2 inhibitory activity (IC50 of 27 μM). Although Les 5740 showed low cytotoxicity in various cancer and normal-like cell lines, the triple-negative breast cancer (TNBC) cell line MDA-MB-231 showed increased susceptibility to this molecule. Les 5740 did not induce DNA damage in mammary cells. At 30 μM, it increased TNBC cells' necrosis. The impact of a non-toxic concentration of Les 5740 (5 μM) on TNBC cell motility was evaluated. Les 5740 reduced 2D chemoinvasion and altered cell morphology. These findings are consistent with a potential reduction in extracellular matrix stiffness as a consequence of LOXL2 inhibition. Les 5740 mildly inhibited tubulin polymerisation, supporting a multi-target profile. Overall, Les 5740 should be viewed as a starting scaffold with LOXL2 inhibitory activity and broader cellular effects, motivating optimisation toward more potent and selective LOXL2 inhibitors for breast cancer therapy.