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

  • J Med Chem. 2024 Dec 26;67(24):21905-21915. doi: 10.1021/acs.jmedchem.4c01747.
Kristoffer Peterson  1 ,  Ulf J Nilsson  1  2 ,  Lise Gravelle  3 ,  Ian Holyer  4 ,  Karl Jansson  5 ,  Barbro Kahl-Knutson  6 ,  Hakon Leffler  6 ,  Alison C MacKinnon  7 ,  James A Roper  4 ,  Robert J Slack  4 ,  Henrik von Wachenfeldt  5 ,  Anders Pedersen  3 ,  Fredrik R Zetterberg  1
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. Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, DK-2200, Copenhagen, Denmark.
  • 4. Galecto Biotech ApS, Stevenage Bioscience Catalyst, Stevenage, Hertfordshire SG1 2FX, U.K.
  • 5. Red Glead Discovery AB, Medicon Village, SE-223 63, Lund, Sweden.
  • 6. Department of Laboratory Medicine, Lund University, Box 124, SE-221 00, Lund, Sweden.
  • 7. Galecto Biotech ApS, Nine Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, U.K.
PMID: 39668131 DOI: 10.1021/acs.jmedchem.4c01747
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 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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