期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 5, 页码 1895-1920出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01449
关键词
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资金
- fund for Scientific Research Flanders (FWO) [G078713N]
- FWO [11Z815N, 11Z817N, 1S42616N]
- Institute for the promotion of Innovation by Science and Technology in Flanders (IWT) [141554]
- Methusalem grant [BOF09/01M00709, BOF16/MET_V/007]
- Vlaams Instituut voor Biotechnologie (VIB)
- Ghent University (MRP)
- Foundation against Cancer [2012-188, FAF-F/2016/865]
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) [FWO G.0875.11, FWO G.0A45.12N, FWO G.0787.13N, FWO G.0C37.14N, FWO G.0E04.16N]
- Flemish Government [BOF09/01M00709, BOF16/MET_V/007]
- Belgian science policy office (BELSPO) [IAP 7/32]
- FWO
- Flemish Government, department EWI
- FWO Excellence of Science program [G0G6618N (EOS ID 30826052)]
- University of Antwerp
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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