Publication
Title
Tozasertib analogues as inhibitors of necroptotic cell death
Author
Abstract
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.
Language
English
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Publication
Washington, D.C. : 2018
ISSN
0022-2623 [print]
1520-4804 [online]
Volume/pages
61:5(2018), p. 1895-1920
ISI
000427331500011
Pubmed ID
29437386
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
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.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 19.03.2018
Last edited 06.09.2021
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