Design and synthesis of proteolysis-targeting chimeras (PROTACs) as degraders of glutathione peroxidase 4

Ferroptosis is a new type of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) has been considered as an effective cancer treatment strategy, but only few GPX4 inhibitors have been reported to date. Targeted protein degradation is receiving increasing attention in the discovery and development of therapeutic modality, particularly proteolysis targeting chimeras (PROTACs). Herein, we reported the design, synthesis, and evaluation of different types of GPX4-targeting PROTACs using ML162 derivatives and ligands for CRBN/VHL E3 ligases. Among them, CRBN-based PROTAC GDC-11 showed a relatively balanced biological profile in GPX4 degradation (degradation rate of 33% at 10 & mu;M), cytotoxicity (IC50 = 11.69 & mu;M), and lipid peroxides accumulation (2-fold increase related to DMSO), suggesting a typical characteristic of ferroptosis. In silico docking and quantum chemistry theoretical calculations provided a plausible explanation for the moderate degrading effect of these synthesized PROTACs. Overall, this work lays the foundation for subsequent studies of GPX4-targeting PROTACs, and further design and synthesis of GPX4-targeting degrader are currently in progress in our group, which will be reported in due course.

Automated summary

Ferroptosis, a newly discovered form of regulated cell death driven by iron-dependent lipid peroxidation, has been proposed as an effective treatment strategy for cancer by inactivating glutathione peroxidase 4 (GPX4). However, the development of GPX4 inhibitors is limited. This study focuses on the design, synthesis, and evaluation of GPX4-targeting proteolysis targeting chimeras (PROTACs), with one of the synthesized PROTACs, CRBN-based PROTAC GDC-11, showing promising potential in inducing ferroptosis in cancer cells. Docking and theoretical calculations provide insights into the moderate degrading effect of these PROTACs. This work lays the foundation for further studies and synthesis of GPX4-targeting degraders.