Ugi reaction-assisted assembly of covalent PROTACs against glutathione peroxidase 4

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Targeting glutathione peroxidase 4 (GPX4) to induce ferroptosis is a promising cancer therapy strategy.
• Limited development of effective GPX4 inhibitors hinders therapeutic progress.
• Proteolysis Targeting Chimera (PROTAC) technology offers a novel approach to drug development.

Purpose of the Study:

• To design and synthesize novel PROTAC-like molecules targeting GPX4 for cancer therapy.
• To evaluate the efficacy of these degraders in promoting GPX4 degradation and inducing ferroptosis.
• To explore the therapeutic potential of GPX4 degraders in cancer treatment.

Main Methods:

• Synthesis of PROTAC-like probe PD-Q2 using Ugi reaction, incorporating a GPX4 inhibitor and a cereblon ligand.
• Development and optimization of heterofunctional PROTAC degraders (PD-4, PD-P2) by varying linker structures.
• Assessment of GPX4 degradation via ubiquitin-proteasome system, lipid reactive oxygen species (ROS) accumulation, and cell proliferation assays.

Main Results:

• PD-Q2 covalently targeted GPX4, but with weak degradation efficiency.
• Synthesized degraders PD-4 and PD-P2 effectively degraded GPX4 through the ubiquitin-proteasome system.
• PD-4 and PD-P2 induced lipid ROS accumulation, inhibited colony formation, and suppressed cell growth.
• Degraders showed lysosomal localization with pomalidomide, potentially impacting anti-proliferation effectiveness.

Conclusions:

• Novel PROTAC-based degraders (PD-4, PD-P2) were successfully developed for targeting GPX4.
• These degraders effectively induce GPX4 degradation and exhibit anti-cancer activity by promoting ferroptosis.
• Further investigation into GPX4 degraders holds therapeutic potential for cancer treatment by modulating ferroptosis.