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

6 Citations (Scopus)

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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Graft vs Host Disease
Proteomics
Cytokine Receptors
Graft Survival
Ulcerative Colitis
Leukemia
Cardiovascular Diseases
Biomarkers
Cytokines
Antibodies
Pharmaceutical Preparations

Keywords

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

Cite this

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). https://doi.org/10.1172/jci.insight.99208

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

In: JCI insight, Vol. 3, No. 14, 26.07.2018.

Research output: Contribution to journalArticle

Ramadan, AM, Daguindau, E, Rech, JC, Chinnaswamy, K, Zhang, J, Hura, GL, Griesenauer, B, Bolten, Z, Robida, A, Larsen, M, Stuckey, JA, Yang, CY & Paczesny, S 2018, 'From proteomics to discovery of first-in-class ST2 inhibitors active in vivo', JCI insight, vol. 3, no. 14. https://doi.org/10.1172/jci.insight.99208
Ramadan AM, Daguindau E, Rech JC, Chinnaswamy K, Zhang J, Hura GL et al. From proteomics to discovery of first-in-class ST2 inhibitors active in vivo. JCI insight. 2018 Jul 26;3(14). https://doi.org/10.1172/jci.insight.99208
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. / From proteomics to discovery of first-in-class ST2 inhibitors active in vivo. In: JCI insight. 2018 ; Vol. 3, No. 14.
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