1 research outputs found
Tozasertib Analogues as Inhibitors of Necroptotic Cell Death
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 <b>71</b> and <b>72</b> outperformed tozasertib in an in vivo
TNF-induced systemic inflammatory response syndrome (SIRS) mouse model