GSK872 Chemical Properties

Boiling point:

625.7±55.0 °C(Predicted)

Density 

1.395±0.06 g/cm3(Predicted)

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

solubility 

Soluble in DMSO (up to at least 25 mg/ml)

pka

5.53±0.49(Predicted)

form 

solid

color 

Off-White or pale yellow

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.

GSK872 Usage And Synthesis

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.

storage

-20°C

References

1)?Kaiser et al. (2013) Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL; J. Biol. Chem.?288 31279 2)?Mandal et al. (2014) RIP3 induces apoptosis independent of pro-necrotic kinase activity; Mol. Cell 56 481

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