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

Abstract

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.