Pharmacological Characterization of GB1908, a Selective Galectin-1 Carbohydrate Binding Domain Inhibitor for the Treatment of Cancer.

Introduction: Galectin-1 (Gal-1) is a lectin that has been shown to be involved in a number of pro-tumorigenic mechanisms and has also been shown to be immune-suppressive. Therefore, pharmacological blockade of Gal-1 has the potential to be therapeutically beneficial in cancers that overexpress this lectin where it is hypothesized to be driving cancer progression.

Methods: GB1908 is a novel, selective and high affinity inhibitor of the Gal-1 carbohydrate recognition domain and in this study, we have pharmacologically characterized this small molecule in a range of in vitro and in vivo systems in the context of cancer therapy. In addition, we used a data-driven approach to identify the cancer types which may benefit from Gal-1 inhibitor therapy.

Results: The selectivity of GB1908 for Gal-1 compared with galectin-3 (Gal-3) was confirmed in biophysical and cellular assays. GB1908 attenuated Gal-1-induced T cell (Jurkat) apoptosis and reduced the production of immunosuppressive cytokines in a stromal non-small cell lung cancer tumor microenvironment model. Breast carcinoma and metastatic skin cutaneous melanoma were identified as cancers in which high Gal-1 expression correlated with poorer survival outcomes in patients. Treatment with GB1908 slowed tumor growth in syngeneic mouse models of these cancers.

Conclusion: The inhibition of both tumor growth and immune-suppressive cytokines, in cancers in which high Gal-1 is associated with poorer survival outcomes, suggests a potential therapeutic benefit for Gal-1 inhibitors such as GB1908.