Heat Shock Protein 90 Interactome-Mediated Proteolysis Targeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4 to Trigger Ferroptosis,Journal of Medicinal Chemistry

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Heat Shock Protein 90 Interactome-Mediated Proteolysis Targeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4 to Trigger Ferroptosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c01518
Jinyun Dong _{1,

2} , Furong Ma ₃ , Maohua Cai ₃ , Fei Cao ₄ , Haobin Li ₃ , Hui Liang ₃ , Yulong Li ₃ , Guangyu Ding _{1,

2} , Juan Li ₁ , Xiangdong Cheng _{1,

2} , Jiang-Jiang Qin _{1,

2}

Affiliation

Targeted protein degradation (TPD) is an emerging therapeutic paradigm aimed at eliminating the disease-causing protein with aberrant expression. Herein, we report a new approach to inducing intracellular glutathione peroxidase 4 (GPX4) protein degradation to trigger ferroptosis by bridging the target protein to heat shock protein 90 (HSP90), termed HSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC). Different series of HIM-PROTACs were synthesized and evaluated, and two of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated ubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC₅₀ values of 0.18 and 0.08 μM, respectively. In particular, GDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor ML162. Moreover, these two degraders effectively suppress tumor growth in the mice model with relatively low toxicity as compared to the combination therapy of GPX4 and HSP90 inhibitors. In general, this study demonstrated the feasibility of degrading GPX4 via HSP90 interactome, and thus provided a significant complement to existing TPD strategies.

中文翻译：

热休克蛋白 90 相互作用组介导的蛋白水解靶向嵌合体（HIM-PROTAC）降解谷胱甘肽过氧化物酶 4 以触发铁死亡

靶向蛋白降解（TPD）是一种新兴的治疗范式，旨在消除表达异常的致病蛋白。在此，我们报道了一种通过桥接靶蛋白与热休克蛋白 90 （HSP90）来诱导细胞内谷胱甘肽过氧化物酶 4 （GPX4）蛋白降解以触发铁死亡的新方法，称为 HSP90 相互作用组介导的蛋白水解靶向嵌合体（HIM-PROTAC）。合成并评价了不同系列的 HIM-PROTACs，其中 GDCNF-2/GDCNF-11 通过 HSP90 介导的 GPX4 泛素-蛋白酶体降解在 HT-1080 细胞中有效诱导铁死亡，DC₅₀ 值分别为 0.18 和 0.08 μM。特别是，GDCNF-11 的铁死亡选择性是 GPX4 抑制剂 ML162 的 15 倍。此外，与 GPX4 和 HSP90 抑制剂的联合治疗相比，这两种降解剂有效抑制小鼠模型中的肿瘤生长，毒性相对较低。总的来说，本研究证明了通过 HSP90 相互作用组降解 GPX4 的可行性，从而为现有的 TPD 策略提供了重要的补充。

更新日期：2024-09-04

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