Browsing by Author "Chinnaswamy, Krishnapriya"

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    From proteomics to discovery of first-in-class ST2 inhibitors active in vivo
    (American Society for Clinical Investigation, 2018-07-26) Ramadan, Abdulraouf M.; Daguindau, Etienne; Rech, Jason C.; Chinnaswamy, Krishnapriya; Zhang, Jilu; Hura, Greg L.; Griesenauer, Brad; Bolten, Zachary; Robida, Aaron; Larsen, Martha; Stuckey, Jeanne A.; Yang, Chao-Yie; Paczesny, Sophie; Pediatrics, School of Medicine
    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.