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Stopping unwanted cell death: Implications for drug discovery
Date:4/13/2008

ted cells, explains Degterev. This work, done in Yuans lab at Harvard, was subsequently awarded patents. The next step, then, was to look for the target of the inhibition by necrostatins to understand how they inhibit necroptosis. We were particularly interested in RIP1 kinase because it was previously reported by other groups to be important for necroptosis and necrostatin-1 looked similar to known kinase inhibitors.

The researchers employed several molecular techniques to determine the role these necrostatins played in inhibiting necroptosis. To test whether necrostatin-1 is a RIP1 kinase inhibitor in vitro, researchers added necrostatin-1 in incremental doses to purified RIPI kinase, and observed a dose-dependent decrease in its activity (phosphorylation). To validate their discovery, the researchers made small and specific structural changes to necrostatin-1, to see if loss of the RIP1 kinase inhibition resulted in the inability of the necrostatin-1 analogs to prevent necrosis. Similar experiments were conducted for necrostatin-3 and necrostatin-5 with similar results, which was surprising as the structure of these two molecules are very different from necrostatin-1. Further, based on the results of their analysis, researchers put forward the model describing mechanisms of RIP1 inhibition by necrostatin-1.

Next, research needs to determine the cellular pathway initiated by RIP1 kinase activity, develop better tools to further investigate its role in human disease, and establish how necrostatins are able to prevent RIP1 kinase from signaling the cell to kill itself, says Degterev. This may one day result in effective therapies, currently not available, for many life-threatening diseases.

These findings on RIP1 kinase inhibitors suggest entirely new possibilities to investigating the role of necroptosis in disease and indicate that these inhibitors may provide ways to prevent extensive tissue damage, says Naomi Rosenberg, PhD, dean at t
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Contact: Siobhan E. Gallagher
siobhan.gallagher@tufts.edu
617-636-6586
Tufts University, Health Sciences
Source:Eurekalert  

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