2. Academic Validation
  3. Structure-Activity relationship of 1-(Furan-2ylmethyl)Pyrrolidine-Based Stimulation-2 (ST2) inhibitors for treating graft versus host disease

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

  • Bioorg Med Chem. 2022 Oct 1:71:116942. doi: 10.1016/j.bmc.2022.116942.
Xinrui Yuan 1,  Hua Jiang 2,  Denggang Fu 2,  Aaron Robida 3,  Krishani Rajanayake 4,  Hebao Yuan 4,  Bo Wen 4,  Duxin Sun 4,  Brennan T Watch 5,  Krishnapriya Chinnaswamy 6,  Jeanne A Stuckey 6,  Sophie Paczesny 2,  Jason C Rech 7,  Chao-Yie Yang 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States.
  • 2 Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States.
  • 3 Life Sciences Institute, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
  • 4 Rogel Cancer Center, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Pharmaceutical Sciences, College of Pharmacy, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
  • 5 Michigan Center for Therapeutic Innovation, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
  • 6 Life Sciences Institute, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Rogel Cancer Center, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
  • 7 Michigan Center for Therapeutic Innovation, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, United States. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States. Electronic address: [email protected].
PMID: 35930851 DOI: 10.1016/j.bmc.2022.116942
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.

Keywords

AlphaLISA; Cytokine; Cytokine receptor; Graft versus host disease; Hematopoietic cell transplantation; IL33; Mixed lymphocyte reaction; Pharmacokinetics; ST2; Small-molecule inhibitor; iST2-1; soluble ST2.

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