Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
Chembiochem. 2022 Jan 5;23(1):e202100253. doi: 10.1002/cbic.202100253. Epub 2021 Jul 22.
The identification of growth inhibitory compounds with the ability to selectively target the cellular oxygenation state may be of therapeutic interest. Here, a phenotypic screen of a covalent fragment library revealed diverse compounds containing propiolamide warheads with selective toxicity for liver cancer cells in normoxic conditions. Target identification and validation through CETSA and direct pulldown experiments demonstrated that several compounds target glutathione peroxidase 4 (GPX4) and induce ferroptotic cell death. Although being an oxidative cell death mechanism, ferroptosis can be induced also under hypoxic conditions. Prompted by the selective toxicity discovered in the screen, we mapped the oxygen-dependence of several ferroptosis-inducing compounds across three different cell lines. These studies revealed combinations with notable reductions in sensitivity under hypoxic conditions. These observations are mechanistically interesting and may be relevant for the use of ferroptosis-inducers as anti-cancer agents.
鉴定具有选择性靶向细胞氧合状态的生长抑制化合物可能具有治疗意义。在这里，对共价片段文库进行表型筛选，发现了多种含有丙炔酰胺弹头的化合物，这些化合物在常氧条件下对肝癌细胞具有选择性毒性。通过 CETSA 和直接下拉实验进行的靶标鉴定和验证表明，几种化合物靶向谷胱甘肽过氧化物酶 4（GPX4）并诱导铁死亡细胞死亡。尽管铁死亡是一种氧化细胞死亡机制，但它也可以在缺氧条件下诱导。受筛选中发现的选择性毒性的启发，我们在三种不同的细胞系中绘制了几种诱导铁死亡化合物的氧依赖性图谱。这些研究揭示了在缺氧条件下具有显著降低敏感性的组合。这些观察结果在机制上很有趣，可能与将铁死亡诱导剂用作抗癌剂有关。
