The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
ACS Chem Biol. 2020 Oct 16;15(10):2702-2713. doi: 10.1021/acschembio.0c00482. Epub 2020 Sep 22.
Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound is a more potent analogue of the published compound 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 . These target engagement studies demonstrate that compound 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 and in cells. Compound also shows efficacy in a murine model of systemic inflammatory response syndrome (SIRS).
细胞坏死是一种炎症形式的程序性细胞死亡，与多种人类疾病有关。化合物是已发表的化合物的更有效的类似物，能以纳摩尔浓度抑制人和鼠细胞的细胞坏死。采用了几种靶标结合策略，包括细胞热转移测定（CETSA）和二氮杂环丁烷介导的光亲和标记，通过衍生自化合物的双功能光亲和探针。这些靶标结合研究表明，化合物以不同的水平和在细胞中结合三种坏死效应蛋白（混合谱系激酶结构域样蛋白（MLKL）、受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）和受体相互作用丝氨酸/苏氨酸蛋白激酶 3（RIPK3））。化合物在系统性炎症反应综合征（SIRS）的小鼠模型中也显示出疗效。
