Laboratory of Medicinal Chemistry , University of Antwerp , Universiteitsplein 1 , Wilrijk-Antwerp 2610 , Belgium.
Molecular Signaling and Cell Death Unit , VIB Center for Inflammation Research , Technologiepark 927 , Zwijnaarde-Ghent 9052 , Belgium.
J Med Chem. 2018 Mar 8;61(5):1895-1920. doi: 10.1021/acs.jmedchem.7b01449. Epub 2018 Feb 20.
Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.
受体相互作用蛋白激酶 1（RIPK1）在肿瘤坏死因子（TNF）诱导的坏死性凋亡中发挥着关键作用，这表明该途径可能具有可药性。大多数 RIPK1 抑制剂被归类为 II 型或 III 型激酶抑制剂。这为发现靶向 RIPK1 活性位点的新型抑制剂开辟了一些有趣的前景。托扎塞替布（tozasertib）是一种 I 型泛极光激酶（AurK）抑制剂，被发现对 RIPK1 具有很高的亲和力。由于 tozasertib 呈现出 I 型激酶抑制剂的典型结构特征，因此 tozasertib 的结构类似物的开发是鉴定新型 I 型 RIPK1 抑制剂的良好起点。在本文中，我们发现了一些有趣的抑制剂，它们能抑制 mTNF 诱导的坏死性凋亡，但对 AurK A 和 B 没有明显影响，因此不会像 tozasertib 那样导致核异常。化合物 71 和 72 在体内 TNF 诱导的全身炎症反应综合征（SIRS）小鼠模型中表现优于 tozasertib。
