Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer

Zetterberg, Fredrik R. ; Peterson, Kristoffer ; Nilsson, Ulf J. LU ; Andréasson Dahlgren, Kajsa ; Diehl, Carl ; Hoyler, Ian ; Håkansson, Maria ; Khabut, Areej LU ; Kahl-Knutson, Barbro LU and Leffler, Hakon LU , et al. (2024) In Journal of Medicinal Chemistry
Abstract
We have previously described a new series of selective and orally
available galectin-1 inhibitors resulting in the thiazole-containing
glycomimetic GB1490. Here, we show that the introduction of polar
substituents to the thiazole ring results in galectin-1-specific
compounds with low nM affinities. X-ray structural analysis of a new
ligand-galectin-1 complex shows changes in the binding mode and
ligand-protein hydrogen bond interactions compared to the
GB1490-galectin-1 complex. These new high affinity ligands were further
optimized with respect to affinity and ADME properties resulting in the
galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited... (More)
We have previously described a new series of selective and orally
available galectin-1 inhibitors resulting in the thiazole-containing
glycomimetic GB1490. Here, we show that the introduction of polar
substituents to the thiazole ring results in galectin-1-specific
compounds with low nM affinities. X-ray structural analysis of a new
ligand-galectin-1 complex shows changes in the binding mode and
ligand-protein hydrogen bond interactions compared to the
GB1490-galectin-1 complex. These new high affinity ligands were further
optimized with respect to affinity and ADME properties resulting in the
galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC50
= 850 nM). Pharmacokinetic experiments in mice revealed that a dose of
30 mg/kg b.i.d. results in free levels of GB1908 in plasma over
galectin-1 Kd for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Journal of Medicinal Chemistry
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38804039
  • scopus:85194404639
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.4c00485
language
English
LU publication?
yes
id
236045e0-059c-48f5-8942-1091ea1476bd
date added to LUP
2024-05-30 17:22:16
date last changed
2024-06-11 09:57:10
@article{236045e0-059c-48f5-8942-1091ea1476bd,
  abstract     = {{We have previously described a new series of selective and orally <br>
available galectin-1 inhibitors resulting in the thiazole-containing <br>
glycomimetic GB1490. Here, we show that the introduction of polar <br>
substituents to the thiazole ring results in galectin-1-specific <br>
compounds with low nM affinities. X-ray structural analysis of a new <br>
ligand-galectin-1 complex shows changes in the binding mode and <br>
ligand-protein hydrogen bond interactions compared to the <br>
GB1490-galectin-1 complex. These new high affinity ligands were further <br>
optimized with respect to affinity and ADME properties resulting in the <br>
galectin-1-selective GB1908 (<i>K</i><sub>d</sub> galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC<sub>50</sub><br>
 = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of <br>
30 mg/kg b.i.d. results in free levels of GB1908 in plasma over <br>
galectin-1 <i>K</i><sub>d</sub> for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.}},
  author       = {{Zetterberg, Fredrik R. and Peterson, Kristoffer and Nilsson, Ulf J. and Andréasson Dahlgren, Kajsa and Diehl, Carl and Hoyler, Ian and Håkansson, Maria and Khabut, Areej and Kahl-Knutson, Barbro and Leffler, Hakon and MacKinnon, Alison C. and Roper, James A. and Slack, Robert J. and Zarrizi, Reihaneh and Pedersen, Anders}},
  issn         = {{1520-4804}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.4c00485}},
  doi          = {{10.1021/acs.jmedchem.4c00485}},
  year         = {{2024}},
}