Ramadan, Abdulraouf M.Daguindau, EtienneRech, Jason C.Chinnaswamy, KrishnapriyaZhang, JiluHura, Greg L.Griesenauer, BradBolten, ZacharyRobida, AaronLarsen, MarthaStuckey, Jeanne A.Yang, Chao-YiePaczesny, Sophie2019-05-012019-05-012018-07-26Ramadan, A. M., Daguindau, E., Rech, J. C., Chinnaswamy, K., Zhang, J., Hura, G. L., … Paczesny, S. (2018). From proteomics to discovery of first-in-class ST2 inhibitors active in vivo. JCI insight, 3(14), e99208. doi:10.1172/jci.insight.99208https://hdl.handle.net/1805/19054Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.en-USPublisher PolicyTherapeuticsTransplantationDrug screensStem cell transplantationTh2 responseArticle