GDAz-3 is a potent GPX4-targeting HSP70-PROTAC, potently and rapidly eliminates GPX4 in HT1080 cells (DC50=0.13 uM), thereby triggering ferroptosis with high selectivity.
GDAz-3 could effectively induce the degradation of GPX4 to varying extents in different cell lines after treatment for 24 h, especially for the B16-F10 cell line, does not significantly affect the level of GPX4 mRNA.
GDAz-3 effectively triggered substantial GPX4 degradation in HT1080 cells at 0.3 uM.
GPX4 degradation effect triggered by GDAz-3 is the result of a direct interaction with the HSP70 chaperone complex, GDAz-3 triggers GPX4 degradation through the UPS and chaperone-mediated autophagy (CMA) dual pathways.
GDAz-3 not only potently inhibited the growth of HT1080 cells in vitro with IC50 values in the low micromolar range, but also showed an effective tumor growth inhibition effect in HT1080 tumor-bearing nude mice without obvious toxicity.