Structure-Activity relationship of 1-(Furan-2ylmethyl)Pyrrolidine-Based Stimulation-2 (ST2) inhibitors for treating graft versus host disease. (1st October 2022)

• Record Type: Journal Article
• Authors: Yuan, Xinrui; Jiang, Hua; Fu, Denggang; Robida, Aaron; Rajanayake, Krishani; Yuan, Hebao; Wen, Bo; Sun, Duxin; Watch, Brennan T.; Chinnaswamy, Krishnapriya; Stuckey, Jeanne A.; Paczesny, Sophie; Rech, Jason C.; Yang, Chao-Yie
• Is Part Of: Bioorganic & medicinal chemistry. Volume 71(2022)
• Publication Date: 2022-10-01
• Subjects: iST2-1 -- ST2 -- IL33 -- Graft versus host disease -- Cytokine -- Cytokine receptor -- Small-molecule inhibitor -- Mixed lymphocyte reaction -- Pharmacokinetics -- AlphaLISA -- soluble ST2 -- Hematopoietic cell transplantation; ST2 Stimulation-2 -- sST2 Soluble ST2 -- GVHD Graft versus Host Disease -- HCT Hematopietic cell transplantation -- MLR Mixed lymphocyte reaction -- Th1 Type 1 helper T cell -- Th2 Type 2 helper T cell -- Treg Regulatory T cell -- PK Pharmacokinetics -- IL-33 Interleukin 33; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116942
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: An elevated plasma level of soluble ST2 (sST2) is a risk biomarker for graft-versus-host disease (GVHD) and death in patients receiving hematopoietic cell transplantation (HCT). sST2 functions as a trap for IL-33 and amplifies the pro-inflammatory type 1 and 17 response while suppressing the tolerogenic type 2 and regulatory T cells activation during GVHD development. We previously identified small-molecule ST2 inhibitors particularly iST2-1 that reduces plasma sST2 levels and improved survival in two animal models. Here, we reported the structure–activity relationship of the furanylmethylpyrrolidine-based ST2 inhibitors based on iST2-1. Based on the biochemical AlphaLISA assay, we improved the activity of iST2-1 by 6-fold (∼6 μM in IC50 values) in the inhibition of ST2/IL-33 and confirmed the activities of the compounds in a cellular reporter assay. To determine the inhibition of the alloreactivity in vitro, we used the mixed lymphocyte reaction assay to demonstrate that our ST2 inhibitors decreased CD4 + and CD8 + T cells proliferation and increased Treg population. The data presented in this work are critical to the development of ST2 inhibitors in future.