The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, GB1211 (h-galectin-3 K_d = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including GB1211 (m-galectin-3 K_d = 0.77 μM). Pharmacokinetic experiments in mouse dosing GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 K_d, which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound, GB2095, was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers.

中文翻译：

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高亲和力选择性半乳糖凝集素-3 小鼠工具化合物在癌症小鼠模型中的开发和表征


在过去几年中，随着几类新化合物的开发，人们对半乳糖凝集素-3 作为癌症和纤维化领域的药物靶标的兴趣有所增加。第一种口服半乳糖凝集素-3 抑制剂 GB1211 （h-半乳糖凝集素-3 K_d = 0.025 μM） 目前处于 2 期临床试验中。由于人和小鼠半乳糖凝集素-3 之间的结构差异，观察到大多数高效的人半乳糖凝集素-3 抑制剂（包括 GB1211）小鼠半乳糖凝集素-3 亲和力显著降低 （m-半乳糖凝集素-3 K_d = 0.77 μM）。小鼠给药 GB1211 高达 100 mg/kg 的药代动力学实验导致游离血浆水平低于 m-半乳糖凝集素-3 K_d，这与在人类中观察到的数据不具有可比性。为了更好地支持转化为临床研究，开发了一种新的改进的小鼠半乳糖凝集素-3 工具化合物 GB2095。将这种新化合物给药于癌症的体内同基因小鼠模型中导致乳腺癌和黑色素瘤的生长减少。