From proteomics to discovery of first-in-class ST2 inhibitors active in vivo
dc.contributor.author | Ramadan, Abdulraouf M. | |
dc.contributor.author | Daguindau, Etienne | |
dc.contributor.author | Rech, Jason C. | |
dc.contributor.author | Chinnaswamy, Krishnapriya | |
dc.contributor.author | Zhang, Jilu | |
dc.contributor.author | Hura, Greg L. | |
dc.contributor.author | Griesenauer, Brad | |
dc.contributor.author | Bolten, Zachary | |
dc.contributor.author | Robida, Aaron | |
dc.contributor.author | Larsen, Martha | |
dc.contributor.author | Stuckey, Jeanne A. | |
dc.contributor.author | Yang, Chao-Yie | |
dc.contributor.author | Paczesny, Sophie | |
dc.contributor.department | Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2019-05-01T14:45:54Z | |
dc.date.available | 2019-05-01T14:45:54Z | |
dc.date.issued | 2018-07-26 | |
dc.description.abstract | Soluble 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_US |
dc.identifier.citation | Ramadan, 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.99208 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/19054 | |
dc.language.iso | en_US | en_US |
dc.publisher | American Society for Clinical Investigation | en_US |
dc.relation.isversionof | 10.1172/jci.insight.99208 | en_US |
dc.relation.journal | JCI Insight | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Therapeutics | en_US |
dc.subject | Transplantation | en_US |
dc.subject | Drug screens | en_US |
dc.subject | Stem cell transplantation | en_US |
dc.subject | Th2 response | en_US |
dc.title | From proteomics to discovery of first-in-class ST2 inhibitors active in vivo | en_US |
dc.type | Article | en_US |