2. Academic Validation
  3. Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia

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

  • J Med Chem. 2022 Apr 28;65(8):5975-5989. doi: 10.1021/acs.jmedchem.1c01296.
Khuchtumur Bum-Erdene 1,  Patrick M Collins 1,  Matthew W Hugo 1,  Somayeh S Tarighat 2,  Fei Fei 2,  Chandan Kishor 1,  Hakon Leffler 3,  Ulf J Nilsson 4,  John Groffen 2,  I Darren Grice 1 5,  Nora Heisterkamp 2,  Helen Blanchard 1
Affiliations

Affiliations

  • 1 Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
  • 2 Section of Molecular Carcinogenesis, Division of Hematology/Oncology and Bone Marrow Transplant, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California 90027, United States.
  • 3 Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84 Lund, Sweden.
  • 4 Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden.
  • 5 School of Pharmacy and Medical Sciences, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
PMID: 35427125 DOI: 10.1021/acs.jmedchem.1c01296
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.

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