From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

Abdulraouf M. Ramadan, Etienne Daguindau, Jason C. Rech, Krishnapriya Chinnaswamy, Jilu Zhang, Greg L. Hura, Brad Griesenauer, Zachary Bolten, Aaron Robida, Martha Larsen, Jeanne A. Stuckey, Chao Yie Yang, Sophie Paczesny

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number14
DOIs
StatePublished - Jul 26 2018

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Keywords

  • Drug screens
  • Stem cell transplantation
  • Th2 response
  • Therapeutics
  • Transplantation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ramadan, A. M., Daguindau, E., Rech, J. C., Chinnaswamy, K., Zhang, J., Hura, G. L., Griesenauer, B., Bolten, Z., Robida, A., Larsen, M., Stuckey, J. A., Yang, C. Y., & Paczesny, S. (2018). From proteomics to discovery of first-in-class ST2 inhibitors active in vivo. JCI Insight, 3(14). https://doi.org/10.1172/jci.insight.99208