Targeting galectin-3 in cancer by novel and unique inhibitors of non-carbohydrate origin

The galactoside-binding galectin-3 is a multi-mode promoter in a broad range of cancers, as well as in the pathogenesis of inflammation and fibrosis-associated diseases. It is currently a hotly pursued therapeutic target in those disease areas. Several carbohydrate-based galectin-3 inhibitors have recently demonstrated encouraging results in early phase clinical trials. This study reports the discovery of two synthetic, non-carbohydrate, small molecule compounds (named K2 an L2) as potent galectin-3 inhibitors. K2 and L2 share the same molecular composition with difference of one -NH2 group located at para (K2) or meta (L2) position at one of its aromatic rings. These novel compound inhibitors were shown to bind to galectin-3 on the canonical S-face of galectin-3 carbohydrate-recognition domain. Their binding was shown to alter galectin-3 conformation and significantly inhibit galectin-3-mediated activities in cancer cell adhesion, invasion, angiogenesis and macrophage secretion of pro-inflammatory cytokines min vitro, and markedly reduce galectin-3-mediated tumour growth and metastasis in vivo in mice as well as in chick embryos. Moreover, these novel galectin-3 inhibitors showed no detectable cytotoxicity and no genotoxicity. K2 and L2 therefore represent a unique class of novel galectin-3 inhibitors that can effectively inhibit galectin-3-mediated activities in vitro and in vivo. The discovery of these non-carbohydrate galectin-3 inhibitors offers significant promises to the development of galectin-3-targeted therapeutic drugs for the treatment of cancer and other galectin-3-mediated pathologies such as inflammation and fibrosis-associated diseases.