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Development and Characterization of a High-Affinity Selective Galectin-3 Mouse Tool Compound in Mouse Models of Cancer

Peterson, Kristoffer LU ; Nilsson, Ulf J. LU ; Gravelle, Lise ; Holyer, Ian ; Jansson, Karl ; Kahl-Knutson, Barbro LU ; Leffler, Hakon LU ; MacKinnon, Alison C. ; Roper, James A. and Slack, Robert J. , et al. (2024) In Journal of Medicinal Chemistry 67(24). p.21905-21915
Abstract

The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, GB1211 (h-galectin-3 Kd = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including GB1211 (m-galectin-3 Kd = 0.77 μM). Pharmacokinetic experiments in mouse dosing GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 Kd, which is not comparable to the data observed in humans. To better... (More)

The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, GB1211 (h-galectin-3 Kd = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including GB1211 (m-galectin-3 Kd = 0.77 μM). Pharmacokinetic experiments in mouse dosing GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 Kd, which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound, GB2095, was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
67
issue
24
pages
21905 - 21915
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85212110459
  • pmid:39668131
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.4c01747
language
English
LU publication?
yes
id
facb966d-64d7-4608-8194-42918f1da2ae
date added to LUP
2024-12-19 18:58:16
date last changed
2025-08-01 22:56:00
@article{facb966d-64d7-4608-8194-42918f1da2ae,
  abstract     = {{<p>The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor,  GB1211 (h-galectin-3 K<sub>d</sub> = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including  GB1211 (m-galectin-3 K<sub>d</sub> = 0.77 μM). Pharmacokinetic experiments in mouse dosing  GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 K<sub>d</sub>, which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound,  GB2095, was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers. </p>}},
  author       = {{Peterson, Kristoffer and Nilsson, Ulf J. and Gravelle, Lise and Holyer, Ian and Jansson, Karl and Kahl-Knutson, Barbro and Leffler, Hakon and MacKinnon, Alison C. and Roper, James A. and Slack, Robert J. and von Wachenfeldt, Henrik and Pedersen, Anders and Zetterberg, Fredrik R.}},
  issn         = {{1520-4804}},
  language     = {{eng}},
  number       = {{24}},
  pages        = {{21905--21915}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Development and Characterization of a High-Affinity Selective Galectin-3 Mouse Tool Compound in Mouse Models of Cancer}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.4c01747}},
  doi          = {{10.1021/acs.jmedchem.4c01747}},
  volume       = {{67}},
  year         = {{2024}},
}