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

Bum-Erdene, Khuchtumur ; Collins, Patrick M. ; Hugo, Matthew W. ; Tarighat, Somayeh S. ; Fei, Fei ; Kishor, Chandan ; Leffler, Hakon LU ; Nilsson, Ulf J. LU ; Groffen, John and Grice, I. Darren , et al. (2022) In Journal of Medicinal Chemistry 65(8). p.5975-5989
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
65
issue
8
pages
15 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85129780054
  • pmid:35427125
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.1c01296
language
English
LU publication?
yes
id
88935f5f-2d4d-4f16-bd62-42217f8dd08f
date added to LUP
2022-09-02 14:58:29
date last changed
2024-06-26 20:47:52
@article{88935f5f-2d4d-4f16-bd62-42217f8dd08f,
  abstract     = {{<p>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.</p>}},
  author       = {{Bum-Erdene, Khuchtumur and Collins, Patrick M. and Hugo, Matthew W. and Tarighat, Somayeh S. and Fei, Fei and Kishor, Chandan and Leffler, Hakon and Nilsson, Ulf J. and Groffen, John and Grice, I. Darren and Heisterkamp, Nora and Blanchard, Helen}},
  issn         = {{0022-2623}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{8}},
  pages        = {{5975--5989}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.1c01296}},
  doi          = {{10.1021/acs.jmedchem.1c01296}},
  volume       = {{65}},
  year         = {{2022}},
}