Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition,Journal of Medicinal Chemistry

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Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-24 , DOI: 10.1021/acs.jmedchem.4c00403
Jian'ai Ji _{1,

2} , Yuhui Jin _{1,

3} , Sinan Ma ₁ , Yuxuan Zhu ₁ , Xinyu Bi ₁ , Qidong You _{1,

3} , Zhengyu Jiang _{1,

3}

Affiliation

Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel–Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe²⁺) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.

中文翻译：

发现一种用于抑制不稳定铁依赖性铁死亡的 NCOA4 降解剂

铁死亡是一种独特的程序性细胞死亡形式，与许多病理状况有关，其抑制被认为是一种有前途的治疗策略。目前，缺乏直接调节细胞内二价铁的有效拮抗剂。铁蛋白自噬是提供细胞内不稳定铁的重要过程，依赖于核受体辅激活剂 4 (NCOA4)，这是铁蛋白铁储存复合物的选择性自噬受体，因此在铁蛋白自噬中发挥着关键作用。在这项研究中，我们报道了一种新型的基于 von Hippel–Lindau 的 NCOA4 降解剂V3 ，它是一种有效的铁死亡抑制剂，具有细胞内亚铁抑制机制。 V3显着降低NCOA4水平并下调细胞内二价铁（Fe ²⁺ ）水平，从而有效抑制细胞内多种途径诱导的铁死亡，减轻肝损伤。这项研究提出了一种针对 NCOA4 的化学敲低工具，用于进一步探索铁死亡中的细胞内亚铁，为铁死亡相关的急性肝损伤提供了一种有前途的治疗途径。

更新日期：2024-07-24

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