Design, synthesis, and biological evaluation of RSL3-based GPX4 degraders with hydrophobic tags

》》文章原文链接：Design, synthesis, and biological evaluation of RSL3-based GPX4 degraders with hydrophobic tags

》》Journal：Eur. J. Med. Chem.

》》相关产品：MG-132 (SJ-BP0049) 和 Chloroquine (SJ-MA0048A)

》》产品引用描述：

》》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 (DC_{50, 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.

》》部分文献数据展示：

Fig. 4：Compound R8 induces degradation of GPX4 through the ubiquitin proteasome-mediated proteolysis process. (A) HT1080 cells in the presence of CHX (200μg/mL) were treated with or without R8 (0.05 μM) where indicated and then GPX4 protein levels were detected at the indicated time points. (B) The quantification of GPX4 level in different groups by gray-scale analysis. (C) Western blot for GPX4 in HT1080 cells after 12 h treatment of R8 with or without MG132 (0.3 μM), or CQ (50 μM). (D) The quantification of GPX4 level in different groups in by gray-scale analysis. (E) Western blot for GPX4 in HT1080 cells after 12 h treatment of RSL3  with or without MG132 (0.3 μM), or CQ (50 μM). (F) The quantification of GPX4 level in different groups by gray-scale analysis.