Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia

摘要

Galectin-3 is a beta-galactoside-specific, carbohydrate-recognizing protein (lectin) that is strongly implicated in cancerdevelopment, metastasis, and drug resistance. Galectin-3 promotes migration and ability to withstand drug treatment of B-cellprecursor acute lymphoblastic leukemia (BCP-ALL) cells. Due to high amino acid conservation among galectins and the shallownature of their glycan-binding site, the design of selective potent antagonists targeting galectin-3 is challenging. Herein, we report thedesign and synthesis of novel taloside-based antagonists of galectin-3 with enhanced affinity and selectivity. The molecules wereoptimized byin silicodocking, selectivity was established against four galectins, and the binding modes were confirmed byelucidation of X-ray crystal structures. Critically, the specific inhibition of galectin-3-induced BCP-ALL cell agglutination wasdemonstrated. The compounds decreased the viability of ALL cells even when grown in the presence of protective stromal cells. Weconclude that these compounds are promising leads for therapeutics, targeting the tumor-supportive activities of galectin-3 in cancer.