Supplementary Material for: 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 (NSCLC) 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.

引言：半乳糖凝集素-1（Galectin-1，Gal-1）是一种凝集素，已被证实参与多种促肿瘤发生机制，且具有免疫抑制作用。因此，在过表达该凝集素且其被假设推动癌症进展的癌症中，对Gal-1进行药理学阻断可能带来治疗获益。
方法：GB1908是一种针对Gal-1碳水化合物识别域的新型、选择性高亲和力抑制剂。本研究在癌症治疗背景下，于多种体外和体内系统中对该小分子进行了药理学表征。此外，我们采用数据驱动方法，确定了可能从Gal-1抑制剂治疗中获益的癌症类型。
结果：在生物物理和细胞实验中，已证实GB1908相对于半乳糖凝集素-3（Gal-3）对Gal-1具有选择性。在基质型非小细胞肺癌（NSCLC）肿瘤微环境模型中，GB1908可减弱Gal-1诱导的T细胞（Jurkat细胞）凋亡，并减少免疫抑制细胞因子的产生。研究发现，乳腺癌和转移性皮肤黑色素瘤中Gal-1高表达与患者较差的生存结局相关。在这些癌症的同基因小鼠模型中，GB1908治疗可减缓肿瘤生长。
结论：在Gal-1高表达与较差生存结局相关的癌症中，GB1908等Gal-1抑制剂可抑制肿瘤生长和免疫抑制细胞因子，这提示其具有潜在治疗获益。