From Inhibition to Degradation: Can Galectin-3 Be Drugged by Heterobifunctional Degraders?

Several nanomolar galectin-3 inhibitors have advanced to clinical evaluation, which suggests that galectin-3 is a druggable target. These small-molecule inhibitors act by binding to the target protein and rely on an occupancy-driven mode of action that may not fully address intracellular functions of galectin-3. Proteolysis-targeting chimaeras (PROTACs) represent an alternative therapeutic modality, enabling intracellular target depletion with an event-driven mode of action. Galectin-3 is present both intracellularly and extracellularly; however, PROTACs can access only the intracellular pool, raising the question of whether selective intracellular degradation can provide sufficient therapeutic benefit. This perspective examines heterobifunctional galectin-3-targeting molecules composed of a glycomimetic ligand, an E3 ligase-recruiting ligand, and a linker. Their structures, degradation-related data, and mechanisms are critically assessed. Key challenges, including linker optimisation, ligand affinity, and intracellular target accessibility, are discussed. A very recent study demonstrated potent and selective galectin-3 degradation and expanded targeted protein degradation to structurally challenging lectins. Overall, galectin-3 represents a proof-of-principle that galectins undergoing intracellular–extracellular trafficking may potentially be degraded by PROTACs.