2. Academic Validation
  3. Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer

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

  • J Med Chem. 2024 Jun 13;67(11):9374-9388. doi: 10.1021/acs.jmedchem.4c00485.
Fredrik R Zetterberg 1,  Kristoffer Peterson 1,  Ulf J Nilsson 1 2,  Kajsa Andréasson Dahlgren 3,  Carl Diehl 4,  Ian Holyer 5,  Maria Håkansson 4,  Areej Khabut 3,  Barbro Kahl-Knutson 6,  Hakon Leffler 6,  Alison C MacKinnon 5,  James A Roper 7,  Robert J Slack 7,  Reihaneh Zarrizi 3,  Anders Pedersen 8
Affiliations

Affiliations

  • 1 Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg,Sweden.
  • 2 Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
  • 3 Red Glead Discovery AB, Medicon Village, SE-223 63 Lund, Sweden.
  • 4 SARomics Biostructures AB, Medicon Village, SE-223 63 Lund, Sweden.
  • 5 Nine Edinburgh Bioquarter, Galecto Biotech ApS, 9 Little France Road, Edinburgh EH16 4UX, U.K.
  • 6 Department of Laboratory Medicine, Lund University, Box 124, SE-221 00 Lund, Sweden.
  • 7 Stevenage Bioscience Catalyst, Galecto Biotech ApS, Stevenage, Hertfordshire SG1 2FX, U.K.
  • 8 Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, DK-2200 Copenhagen, Denmark.
PMID: 38804039 DOI: 10.1021/acs.jmedchem.4c00485
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 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162561
    Galectin-1抑制剂
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