Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).

中文翻译：

---

通过同时靶向途径的多个效应子来有效抑制坏死病。

坏死病是一种编程性细胞死亡的炎性形式，已与多种人类疾病有关。化合物2是已公开化合物1的更有效类似物，并在纳摩尔浓度下抑制人和鼠细胞的坏死。使用了几种目标参与策略，包括细胞热位移分析（CETSA）和通过衍生自化合物2的双功能光亲和探针对二嗪胺介导的光亲和标记。这些目标参与研究表明，化合物2在体外以不同水平结合所有三种坏死性效应蛋白（混合谱系激酶域样蛋白（MLKL），受体相互作用的丝氨酸/苏氨酸蛋白激酶1（RIPK1）和受体相互作用的丝氨酸/苏氨酸蛋白激酶3（RIPK3））和在细胞中。化合物2还在全身性炎症反应综合征（SIRS）的鼠模型中显示了体内功效。