Necroptosis is a form of programmed cell death that contributes to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury. In this study, bardoxolone (CDDO, 7) was an inhibitor of necroptosis identified from an in-house natural product library. Further optimization led to identify a more potent analogue 20. Compound 20 could effectively protect against necroptosis in human and mouse cells. The antinecroptotic effect could also be synergized with other necroptosis inhibitors. It blocked necrosome formation by targeting Hsp90 to inhibit the phosphorylation of RIPK1 and RIPK3 in necroptotic cells. In vivo, this compound was orally active to alleviate TNF-induced systemic inflammatory response syndrome (SIRS) and cerebral I/R injury. Our results suggested that 20 could be a lead compound for discovering necroptosis inhibitors in I/R treatment.

坏死病是程序性细胞死亡的一种形式，有助于脑缺血/再灌注（I / R）损伤的病理生理。在这项研究中，巴多索隆（CDDO，7）是从内部天然产物库中鉴定出的坏死病抑制剂。进一步的优化导致确定了更有效的类似物20。化合物20可以有效预防人类和小鼠细胞的坏死病。抗肿瘤作用也可以与其他坏死抑制剂协同作用。它通过靶向Hsp90抑制坏死性细胞中RIPK1和RIPK3的磷酸化来阻断坏死体的形成。在体内，该化合物具有口服活性，可减轻TNF引起的全身炎症反应综合征（SIRS）和脑I / R损伤。我们的研究结果表明20可能是在I / R治疗中发现坏死性抑制剂的先导化合物。