Identification and Studies of Highly Potent and Selective Heterobifunctional Galectin‑3 Degraders.

On the basis of an X-ray cocrystal structure of our previously disclosed monosaccharide-derived galectin-3 inhibitor 3 with human galectin-3 protein, we envisioned that galectin-3 could be an appropriate target for targeted protein degradation as a potential novel drug discovery strategy. The identification and studies of a series of potent, metabolically stable, cell permeable, and noncytotoxic galectin-3 degraders, represented by 5 and 6, are herein reported. These compounds were highly effective in inducing galectin-3 degradation in normal human lung fibroblast (NHLF), A549, and LL29 cells with a degradation half effective concentration (DC50) value of 4 nM for 5 in NHLF cells. Global proteomics analysis of 6 revealed that the galectin-3 degrader was exquisitely selective for galectin-3 over >7800 other proteins quantified that include galectin family members. To the best of our knowledge, targeted protein degradation of galectin-3 or any other lectin has not been reported in the past.