Identification and Studies of Highly Potent and Selective Heterobifunctional Galectin-3 Degraders
Chunjian Liu, Wei Wang, Aaron J. Balog, Sarah Traeger, Manoranjan Panda, Narasimharaju Kalidindi, Ari Salinger, Yuka Amako, Ashok R. Dongre, Gregory Locke, Fei Yu, John A. Newitt, Susan E. Kiefer, Joseph Naglich, Dong Cheng, Harinath Sale, Bruce A. Ellsworth, Alicia Regueiro-RenAbstract
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.