Heat Shock\nProtein\n90 Interactome-Mediated Proteolysis\nTargeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4\nto Trigger Ferroptosis

Targeted protein degradation (TPD)\nis an emerging therapeutic paradigm\naimed at eliminating the disease-causing protein with aberrant expression.\nHerein, we report a new approach to inducing intracellular glutathione\nperoxidase 4 (GPX4) protein degradation to trigger ferroptosis by\nbridging the target protein to heat shock protein 90 (HSP90), termed\nHSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC).\nDifferent series of HIM-PROTACs were synthesized and evaluated, and\ntwo of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated\nubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC<sub>50</sub> values of 0.18 and 0.08 μM, respectively. In particular,\nGDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor\nML162. Moreover, these two degraders effectively suppress tumor growth\nin the mice model with relatively low toxicity as compared to the\ncombination therapy of GPX4 and HSP90 inhibitors. In general, this\nstudy demonstrated the feasibility of degrading GPX4 via HSP90 interactome,\nand thus provided a significant complement to existing TPD strategies.