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

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