GW4869, a Noncompetitive Neutral Sphingomyelinase (N-SMase) Inhibitor

GW4869 was identified as a noncompetitive inhibitor of the enzyme neutral, magnesium-dependent sphingomyelinase (SMase) more than a decade ago.

A study from Chiara Luberto identified and verified the function of GW4869 in vitro via cell experiments. Treatment of 10 μM GW4869 significantly inhibited TNF-induced SM hydrolysis. And the concentration of  20 μM protected completely from the loss of SM. The addition of GW4869 (10 and 20 μM) completely inhibited the initial accumulation of ceramide, whereas this effect was partially lost at later time points (24 h). Meanwhile, GW4869 showed a dose-dependent manner, to significantly protect from nuclear condensation after TNF treatment, as evaluated by DNA staining with Hoechst. In fact, after 20 h of treatment with TNF, 81% of the cells appeared positive for chromatin condensation, whereas the presence of 10 and 20 μM M GW4869 during the incubation reduced this percentage to 57.2 and 34%, respectively.

Another study from Kobina Essando verified the function of GW4869 in animal models. As a result, GW4869 (2.5 μg/g, i.p.) caused inhibition of exosome release blocked LPS-stimulated pro-inflammatory cytokine production and cardiac inflammation in mice. Meanwhile, GW4869 mitigateed LPS-caused myocardial dysfunction and improves survival in mice. GW4869 (2.5 μg/g, i.p.) also blocks the production of pro-inflammatory cytokines and cardiac inflammation in CLP mice.

Furthermore, GW4869 also could reverse the inhibition of CCN2 3’-UTR activity by miR-214-enriched exosomes in hepatic stellate cells.

To conclude, GW4869 functions as an exosome inhibitor.

1. Luberto C, et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem. 2002 Oct 25;277(43):41128-39.

2. Essandoh K, et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015 Nov;1852(11):2362-71.