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.

Collins, Patrick M.Griffith University (author)
Hugo, Matthew W.Griffith University (author)
Tarighat, Somayeh S.Children's Hospital Los Angeles (author)
Fei, FeiChildren's Hospital Los Angeles (author)
Kishor, ChandanGriffith University (author)
Leffler, HakonLund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)mmb-hle (author)
Nilsson, Ulf J.Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)ok2-uni (author)
Groffen, JohnChildren's Hospital Los Angeles (author)
Grice, I. DarrenGriffith University (author)
Heisterkamp, NoraChildren's Hospital Los Angeles (author)
Blanchard, HelenGriffith University (author)
Griffith UniversityChildren's Hospital Los Angeles (creator_code:org_t)

In:Journal of Medicinal Chemistry: American Chemical Society (ACS)65:8, s. 5975-59890022-26231520-4804

By the author/editor: Bum-Erdene, Khuc ...; Collins, Patrick ...; Hugo, Matthew W.; Tarighat, Somaye ...; Fei, Fei; Kishor, Chandan; show more...; Leffler, Hakon; Nilsson, Ulf J.; Groffen, John; Grice, I. Darren; Heisterkamp, Nor ...; Blanchard, Helen; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

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