GW4869

GW4869 is a noncompetitive neutral sphingomyelinase (N-SMase) inhibitor with an IC₅₀ of 1 μM. GW4869 is an inhibitor of exosome biogenesis/release^[1][2][3][4]. IC50 & Target:IC50: 1 μM (neutral sphingomyelinase)^[1] In Vitro:GW4869 (10 μM) partially inhibits TNF-induced sphingomyelin (SM) hydrolysis, and 20 μM of the compound is protected completely from the loss of SM. The addition of 10-20 μM GW4869 completely inhibits the initial accumulation of ceramide, whereas this effect is partially lost at later time points (24 h). The action of GW4869 occurs downstream of the drop in glutathione. GW4869 is able, in a dose-dependent manner, to significantly protect from cell death^[1].
GW4869 (10 or 20 μM) inhibits both exosome release and pro-inflammatory cytokine production in macrophages. GW4869 inhibits the ceramide-mediated inward budding of multivesicular bodies (MVBs) and release of mature exosomes from MVBs^[2].
GW4869 also could reverse the inhibition of CCN2 3’-UTR activity by miR-214-enriched exosomes in hepatic stellate cells^[3].
Solution Attention: GW4869 is routinely stored at 80 °C as a stock suspension in DMSO. Before cell culture, the stock solution is diluted with culture medium to form a working solution, which can be completely dissolved. In Vivo:GW4869 (2.5 μg/g, i.p.) causes inhibition of exosome release blocks LPS-stimulated pro-inflammatory cytokine production and cardiac inflammation in mice. GW4869 mitigates LPS-caused myocardial dysfunction and improves survival in mice^[2].
GW4869 (2.5 μg/g, i.p.) blocks the production of pro-inflammatory cytokines and cardiac inflammation in CLP mice^[2].