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
  • 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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