Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors.

Autor:	Yuan X; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Jiang H; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina 29425-2503, United States., Fu D; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina 29425-2503, United States., Rech JC; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Robida A; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Rajanayake K; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Yuan H; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., He M; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Wen B; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Sun D; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Liu C; Department of Pathology, Yale University, New Haven, Connecticut 06520, United States., Chinnaswamy K; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Stuckey JA; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Michigan Center for Therapeutic Innovation, Department of Internal Medicine, Life Sciences Institute, Department of Pharmaceutical Sciences, College of Pharmacy, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Paczesny S; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina 29425-2503, United States., Yang CY; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2023 Aug 16; Vol. 6 (9), pp. 1275-1287. Date of Electronic Publication: 2023 Aug 16 (Print Publication: 2023).
DOI:	10.1021/acsptsci.3c00122
Abstrakt:	Hematopoietic cell transplantation (HCT) is a proven and potentially curable therapy for hematological malignancies and inherited hematological disease. The main risk of HCT is the development of graft versus host disease (GVHD) acquired in up to 50% of patients. Upregulation of soluble ST2 (sST2) is a key clinical biomarker for GVHD prognosis and was shown to be a potential therapeutic target for GVHD. Agents targeting sST2 to reduce the sST2 level after HCT have the potential to mitigate GVHD progression. Here, we report 32 (or XY52 ) as the lead ST2 inhibitor from our optimization campaign. XY52 had improved inhibitory activity and metabolic stability in vitro and in vivo. XY52 suppressed proinflammatory T-cell proliferation while increasing regulatory T cells in vitro. In a clinically relevant GVHD model, a 21-day prophylactic regimen of XY52 reduced plasma sST2 and IFN-γ levels and GVHD score and extended survival in mice. XY52 represented a significant improvement over our previous compound, iST2-1 , and further optimization of XY52 is warranted. The small-molecule ST2 inhibitors can potentially be used as a biomarker-guided therapy for mitigating GVHD in future clinical applications. Competing Interests: The authors declare no competing financial interest. (© 2023 American Chemical Society.)
Databáze:	MEDLINE
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