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

Abstract

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.

Strong Binding of C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds

“…All four inhibitors bind by anchoring their β-galactoside part (referred to as Gly-1; see Table ) at subsite C, forming hydrogen-bond interactions with side-chain atoms of His158, Asn160, Arg162, Asn174, and Glu184 and stacking interactions with the side chain of Trp181. This structural mode of binding of the Gly-1 ring to galectin-3 is very similar to the binding of the galactose ring of lactose, TDG, and most disaccharide ligands to galectin-3. ,− The second sugar ring (referred to as Gly-2; Table ) of all four inhibitors, binds partly at subsite D, with 13 , 14 , 15 , and 17 adopting similar conformations. The dihedrals of the thioglycosidic linkage, O5–C1–C2′–C3′, O5–C1–C2′–C1′, C2–C1–C2′–C3′, and C2–C1–C2′–C1′, have values between 57 to 64°, −133 to −142°, −56 to 66°, and 97 to 105°, respectively.…”

“…The structural elements that lead to the higher potency of the four studied inhibitors than that of lactose and TDG might be attributed to van der Waals contacts in subsite D. However, the rather large enthalpy gain might be due to additional factors, such as solvation differences and water-mediated hydrogen bonding, which can lead to enthalpy gains together with compensating entropy penalties. Thus, lactose and TDG form 5 hydrogen-bond interactions with water molecules when bound to galectin-3 , while 13 , 14 , 15 , and 17 form 9, 9, 8, and 7, respectively (Table ). It should be noted that 13 forms more hydrogen bonds than 14 but less van der Waals interactions, and yet 13 exhibits a weaker affinity.…”

Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Galectin-3 and Galectin-8 C-Terminal Domain Inhibitors

“…The acylsulfonyl amide segment constructed charge–charge interactions and hydrogen binding interactions with Arg144 and Arg162, and these interactions directed the arylsulfonamide extending into a somewhat shallow but unique subpocket to gal-3. It was suggested that this area could be utilized to discover new inhibitors with gal-3 selectivity …”

“…As a result, the 4-aryl-1,2,3-triazole thiodigalactoside derivative TD139 (also known as GB0139) was successfully developed and is currently in a phase IIb clinical study as an inhaled treatment for idiopathic pulmonary fibrosis (IPF) . Due to the high polarity and limited oral bioavailability of the disaccharides, the investigation focus was turned to the development of monogalactose-based derivatives, − and a highly selective, orally available monosaccharide gal-3 inhibitor GB1211 was discovered, and it is now in a phase IIa clinical trial for the treatment of liver fibrosis and cancer …”

Inhibition of galectins in cancer: Biological challenges for their clinical application

“…The first described galectin inhibitors are molecules capable of binding to the CRD and preventing further ligand binding. Galectin inhibitors based on these competitive interactions consist of chemically modified mono or disaccharides structured around galactose ( 58 , 122 – 125 ), lactose ( 58 , 125 – 127 ), thiodigalactose (TDG) ( 34 , 128 – 132 ), talose ( 133 , 134 ) and lactulose ( 135 ). One of the first tempts to use this type of inhibitor in cancer consisted of administering a β-D-lactosyl-steroid.…”