GSK840 is a RIPK3 Inhibitor

Necroptosis is a programmed necrosis or inflammatory cell death. It is different from apoptosis. Necroptosis is due to cellular damage or infiltration by pathogens. It is a component of inflammatory diseases such as pancreatitis, Crohn’s disease, and myocardial infarction.

RIP3 (Receptor-interacting serine/threonine-protein kinase 3) is a member of RIP family. It is a part of TNF receptor-I signaling complex. RIP3 also causes apoptosis and shows a weak effect on NF-κB activation. RIP3 plays a central role in necroptosis, controls inflammatory disease.

In the last few years, scientists have been working on discovering the selective RIP3 inhibitors. Thanks to their efforts, we finally make full use of achievement.

PratyushaMandal, et al found out several RIP3 inhibitors, such as GSK’657, GSK’843 and GSK’840 (GSK840). The last is more potent than the former two compounds.

To our delight, GSK840 effectively inhibits recombinant RIP3 kinase activity, with an IC50 of 0.3 nM. In the binding assay, GSK840 has an IC50 of 0.9 nM for RIP3. GSK840 shows no effect on RIP1.

Moreover, GSK840 displays species differences. It is active in human but inactive in mouse cells.

Thus, GSK840 may play an important role in disorders related to RIP3 in human cells. In mouse cells expressing wild type or mutant human hRIP3, GSK840 induces apoptosis in a concentration-dependent manner.

GSK840 is a potent and selective RIP3 inhibitor. Scientists have to do further study to explore more potential of GSK840.

1. Mandal P, et al. Mol Cell. 2014 Nov 20;56(4):481-95.