We have previously identified a small molecule, SF-7044, targeted to the ED (Glu160/Asp-161) substrate-docking domain of p38alpha MAPK rather than the catalytic site. SF-7044 (Fig. 1) was converted to its dihydrochloride dihydrate salt, GEn-1124, to improve its solubility and stability. GEn-1124 stabilizes endothelial barrier, reduces expression of proinflammatory genes, preserves expression of anti- inflammatory genes, and improves survival in mouse models of acute lung injury. GEn-1124 has completed Phase I clinical testing and a Phase II clinical trial is in progress. This study defines the novel mechanism of GEn-1124 in contrast with p38 catalytic site inhibitors.