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An Orally Available Halothiazole Glycomimetic as a Cancer-Targeting Dual Galectin-1 and Galectin-3 Inhibitor

Zetterberg, Fredrik R. ; Peterson, Kristoffer ; Nilsson, Ulf J. LU orcid ; Diehl, Carl ; Håkansson, Maria ; Kahl-Knutson, Barbro LU ; MacKinnon, Alison C. ; Klein, Hanna ; Leffler, Hakon LU and Roper, James A. , et al. (2026) In Journal of Medicinal Chemistry 69(9). p.10494-10514
Abstract

Inhibition of several of the 10 hallmarks of cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined galectin-1/3 inhibitor would be beneficial. Specificity toward galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in GB1841... (More)

Inhibition of several of the 10 hallmarks of cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined galectin-1/3 inhibitor would be beneficial. Specificity toward galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in GB1841 (Kd galectin-1/-3 0.027/0.14 μM). Both selective and dual inhibition of galectin-1 and galectin-3 significantly reduces the growth of LL/2 lung cancer cells in a syngeneic mouse model, supporting further development of GB1841 as a dual inhibitor of galectin-1 and galectin-3.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
69
issue
9
pages
21 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:42052938
  • scopus:105038635849
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.5c03703
language
English
LU publication?
yes
id
b130c29d-88a7-444d-ade3-e576c427f5bf
date added to LUP
2026-05-01 11:03:04
date last changed
2026-05-27 10:20:24
@article{b130c29d-88a7-444d-ade3-e576c427f5bf,
  abstract     = {{<p>Inhibition of several of the 10 hallmarks of cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined galectin-1/3 inhibitor would be beneficial. Specificity toward galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in  GB1841 (<i>K</i><sub>d</sub> galectin-1/-3 0.027/0.14 μM). Both selective and dual inhibition of galectin-1 and galectin-3 significantly reduces the growth of LL/2 lung cancer cells in a syngeneic mouse model, supporting further development of  GB1841 as a dual inhibitor of galectin-1 and galectin-3.</p>}},
  author       = {{Zetterberg, Fredrik R. and Peterson, Kristoffer and Nilsson, Ulf J. and Diehl, Carl and Håkansson, Maria and Kahl-Knutson, Barbro and MacKinnon, Alison C. and Klein, Hanna and Leffler, Hakon and Roper, James A. and Slack, Robert J. and Wachenfeldt, Henrik von and Pedersen, Anders}},
  issn         = {{1520-4804}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{9}},
  pages        = {{10494--10514}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{An Orally Available Halothiazole Glycomimetic as a Cancer-Targeting Dual Galectin-1 and Galectin-3 Inhibitor}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.5c03703}},
  doi          = {{10.1021/acs.jmedchem.5c03703}},
  volume       = {{69}},
  year         = {{2026}},
}