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An overview of GPX4-targeting TPDs for cancer therapy
Xiaojuan Yang1, Liqiang Wu2, Shaohong Xu1
1School of Pharmacy, Xinxiang University, Xinxiang 453003, China.
Abstract:
Ferroptosis is a newly identified form of regulated, non-apoptotic cell death caused by iron-dependent phospholipid peroxidation. Glutathione peroxidase 4 (GPX4) inactivation-induced ferroptosis is an efficient antitumor treatment. Currently, several GPX4 inhibitors have been identified. However, these inhibitors exhibit low selectivity and poor pharmacokinetic properties that preclude their clinical use. Targeted protein degradation (TPD) is an efficient strategy for discovering drugs and has unique advantages over target protein inhibition. Given GPX4's antitumor effects and the potential of TPD, researchers have explored GPX4-targeting TPDs, which outperform conventional inhibitors in several aspects, such as increased selectivity, strong anti-proliferative effects, overcoming drug resistance, and enhancing drug-like properties. In this review, we comprehensively summarize the progress in GPX4-targeting TPDs. In addition, we reviewed the changes and challenges related to the development of GPX4-targeting TPDs for cancer therapy.
Insights
Targeted protein degradation (TPD) offers a promising strategy to induce ferroptosis, a cell death pathway crucial for cancer therapy. GPX4-targeting TPDs show enhanced selectivity and efficacy over traditional inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ferroptosis is a regulated cell death pathway driven by iron-dependent lipid peroxidation.
- Glutathione peroxidase 4 (GPX4) inactivation triggers ferroptosis and shows potential as an antitumor strategy.
- Existing GPX4 inhibitors lack clinical utility due to poor selectivity and pharmacokinetics.
Purpose of the Study:
- To review advancements in targeted protein degradation (TPD) strategies for GPX4.
- To highlight the advantages of GPX4-targeting TPDs over conventional inhibitors in cancer therapy.
- To discuss challenges and future directions in developing GPX4-targeting TPDs.
Main Methods:
- Literature review of studies on ferroptosis and targeted protein degradation.
- Analysis of GPX4 inhibitors and GPX4-targeting TPDs.
- Comparison of efficacy, selectivity, and pharmacokinetic properties.
Main Results:
- GPX4-targeting TPDs demonstrate superior selectivity and anti-proliferative effects compared to traditional inhibitors.
- TPD approaches can overcome drug resistance and improve drug-like properties.
- Significant progress has been made in developing GPX4-targeting TPDs for cancer treatment.
Conclusions:
- GPX4-targeting TPDs represent a promising therapeutic avenue for cancer treatment.
- Further research is needed to address challenges in clinical development and application.
- TPD offers a powerful platform for next-generation cancer therapies targeting ferroptosis.
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