Description
GSK 872 (CAS 1346546-69-7) is a potent (IC50 = 1.8nM domain binding; IC50 = 1.3 nM kinase activity) and selective inhibitor of receptor interacting protein 3 (RIP3).1 It is able to prevent necroptosis, virus-induced necrosis, and TLR3-induced necrosis.1,2 GSK872 can induce Caspase8-mediated apoptosis at higher concentrations (e.g.3 μM).2
Uses
GSK''872 is a potent and selective receptor activating protein kinase 3 (RIP3) inhibitor (IC50 = 1.3 nM). Exhibits >1000-fold selectivity for RIP3 over a panel of 300 other kinases including RIP1. Inhibits TNF-induced cell death in 3T3-SA cells and TLR3-induced necrosis in fibroblasts in vitro. Blocks necroptosis of primary human neutrophils from whole blood. Also induces apoptosis at higher concentrations (3 - 10 μM).
Biological Activity
GSK'872 (GSK2399872A) is a potent and selective RIP3 kinase inhibitor which binds RIP3 kinase domain with high affinity (IC50=1.8 nM) and inhibits kinase activity with IC50 of 1.3 nM. It has minimal cross-reactivity.
in vitro
When assayed at 1 μM, GSK'872 fails to inhibit most of 300 human protein kinases tested. It fails to inhibit RIP1 kinase when tested directly. GSK'872 blocks TNF-induced necroptosis in a concentration-dependent manner in HT-29 cells. In cell-based assays, there is a 100- to 1000-fold shift in the IC50 compared to the cell-free biochemical assays. GSK'872 also blocks necroptosis in primary human neutrophils isolated from whole blood. GSK'872 inhibits TLR3- or DAI-induced death, two RIP1-independent pathways of necroptosis. It induces caspase activation followed by apoptotic cell death.
in vivo
GSK'872 treatment significantly decreases HIF-1α expression compared with no treatment after ischemia injury in vivo.
Background
GSK872 is a potent, selective inhibitor of RIP3 with an IC50 value of 1.8 nM and inhibits kinase activity with an IC50 value of 1.3 nM. RIP3 is required for necroptosis. When this compound is tested at 1 µM, it shows >1,000-fold specificity for RIP3 compared with over 300 kinases tested. GSK872 inhibits both virus-, TNF- and TLR-3-induced necrosis in fibroblasts.
References
[1] WILLIAM J KAISER. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.[J]. The Journal of Biological Chemistry, 2013, 288 43: 31268-31279. DOI:
10.1074/jbc.m113.462341[2] RIP3 induces apoptosis independent of pro-necrotic kinase activity
