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Published on: November 9, 2020
Design, synthesis, and biological evaluation of RSL3-based GPX4 degraders with hydrophobic tags
Yao Ning1, Zeqi Zhu1, Yicheng Wang1
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, PR China.
Abstract:
Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation, during which glutathione peroxidase 4 (GPX4) plays an essential role and is well-recognized as a promising therapeutic target for cancer treatment. Although some GPX4 degradation molecules have been developed to induce ferroptosis, the discovery of GPX4 degraders with hydrophobic tagging (HyT) as an innovative approach is more challenging. Herein, we designed and synthesized a series of HyT degraders by linking the GPX4 inhibitor RSL3 with a hydrophobic and bulky group of adamantane. Among them, compound R8 is a potent degrader (DC50, 24h = 0.019 μM) which can effectively degrade GPX4 in a dose- and time-dependent manner. Furthermore, compound R8 exhibited superior in vitro antitumor potency against HT1080 and MDA-MB-231 cell lines with IC50 values of 24 nM and 32 nM respectively, which are 4 times more potent than parental compound RSL3. Mechanistic investigation evidenced that R8 consumes GPX4 protein mainly through the ubiquitin proteasome (UPS) and enables to induce the accumulation of LPO, thereby triggering ferroptosis. Our work presented the novel GPX4 degrader of R8 by HyT strategy, and provided a promising pathway of degradation agents for the treatment of ferroptosis relevant diseases.
Insights
Researchers developed a novel ferroptosis inducer, R8, using hydrophobic tagging to degrade glutathione peroxidase 4 (GPX4). This potent GPX4 degrader shows enhanced anti-cancer activity, offering a new therapeutic strategy for ferroptosis-related diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ferroptosis is programmed cell death driven by iron-dependent lipid peroxidation.
- Glutathione peroxidase 4 (GPX4) is crucial in ferroptosis and a key cancer therapeutic target.
- Developing GPX4 degraders via hydrophobic tagging (HyT) presents a novel but challenging approach.
Purpose of the Study:
- To design and synthesize novel GPX4 degraders using the HyT strategy.
- To evaluate the efficacy and potency of these new degraders in cancer treatment.
- To elucidate the mechanism of action for the most potent degrader.
Main Methods:
- Synthesis of adamantane-linked GPX4 inhibitor (RSL3) derivatives.
- Assessment of GPX4 degradation using compound R8 in cancer cell lines.
- In vitro evaluation of antitumor activity and IC50 values.
- Mechanistic studies involving the ubiquitin-proteasome system (UPS) and lipid peroxidation (LPO).
Main Results:
- Compound R8 demonstrated potent GPX4 degradation (DC50, 24h = 0.019 μM) in a dose- and time-dependent manner.
- R8 exhibited significantly enhanced in vitro antitumor potency against HT1080 and MDA-MB-231 cells (IC50 = 24 nM and 32 nM, respectively), outperforming RSL3.
- R8 induces ferroptosis by degrading GPX4 via the UPS, leading to LPO accumulation.
Conclusions:
- The novel HyT strategy successfully generated potent GPX4 degraders, exemplified by compound R8.
- Compound R8 represents a promising therapeutic agent for ferroptosis-relevant diseases, including cancer.
- This work establishes a new pathway for developing degradation agents targeting GPX4.
