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Tozasertib analogues as inhibitors of necroptotic cell death
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| Abstract |
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| 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. |
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English
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Journal of medicinal chemistry. - Washington, D.C., 1963, currens | |
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Washington, D.C. : 2018
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0022-2623 [print]
1520-4804 [online]
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| Volume/pages |
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61:5(2018), p. 1895-1920
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000427331500011
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29437386
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Identification, lead optimization and validation of necroptosis inhibitors. High-end molecular dynamics simulations combined with click chemistry synthesis to develop novel therapeutic compounds starting from small molecule fragments. Computational investigations of the catalytic mechanism of Staphylococcus aureus transglycosylase: design and chemical synthesis of novel mechanism-based inhibitors.
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Publications with a UAntwerp address
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19.03.2018
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| Last edited |
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06.09.2021
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