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

Mean biomass-per-unit-effort (BPUE) of the eleven most commonly caught species from 2007–2013.

<p>BPUE is represented as the estimated weight (kg) of fishes caught-per-angler-hour, using two hooks per line. Solid lines illustrate catch rates from marine protected areas (MPA), whereas dashed lines represent values from associated reference (REF) sites. Error bars denote one standard error above and below the mean.</p