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. Epub 2024 Dec 12.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Blood Proteins / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Galectin 3* / antagonists & inhibitors
  • Galectin 3* / metabolism
  • Galectins / antagonists & inhibitors
  • Galectins / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Structure-Activity Relationship

Substances

  • Galectin 3
  • Antineoplastic Agents
  • Galectins
  • Blood Proteins
  • Lgals3 protein, mouse