# Development of first-in-class ST2 inhibitors for treating graft-versus-host disease

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $650,311

## Abstract

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for blood related cancers
including leukemia, lymphomas, and multiple myeloma. Its clinical success has been limited by the frequent
development of severe and life-threatening acute graft versus host disease (aGVHD). Although monitoring of
prognostic plasma biomarkers enables clinicians to stratify high-risk patients at onset of aGVHD for aggressive
therapy, no drug has been specifically developed for aGVHD and subsequently approved to date. Among the
aGVHD biomarkers, elevated levels of soluble STimulation-2 (sST2, ST2 is also named IL33Rc) is the most
significant factor to predict steroid-resistant aGVHD that leads to non-relapse related death. sST2, functioning
as a decoy receptor, traps IL-33 to reduce secretion of type-2 cytokines and contributes to overt pro-
inflammatory type-1 immunity in aGVHD development. Our central hypothesis is that sST2 can be a
therapeutic target and blockade of sST2/IL-33 interaction is a novel strategy to ameliorate aGVHD. To support
the hypothesis, we have reported that peritransplant administration of ST2 neutralizing antibody in mice leads
to decreased sST2 production and increased number of Th2 and Tregs cells post-transplantation resulting in
alleviated aGVHD and improved survival. Motivated by the same objective, we recently completed a project to
discover three chemical classes of small molecule ST2 inhibitors by employing high throughput screening and
computational analysis. When evaluated in mouse aGVHD models, one compound produces the best outcome
including improved survival, reduced plasma levels of sST2 and undiminished graft-versus-leukemia effect.
The rationale of this study is that our lead compounds can be further optimized for pre-clinical therapeutic
development including advancement to orally bioavailable agents, infeasible for antibody-based therapeutics.
In this study, the three specific aims are: 1) To design and synthesize new analogs based on one lead
compound with the aim of improving its potency, selectivity, and physicochemical properties for in vivo studies.
2) Determination of in vitro stability/toxicity of the inhibitors and their activities in the in vitro aGVHD assay. 3)
Assessment of in vivo absorption, distribution, metabolism, and excretion (ADME)/Toxicity of the inhibitors and
their efficacies in aGVHD mouse models. Current aGVHD therapy adopts drugs designed for other diseases
and these drugs target non-specific effector T cells. Our innovative approach builds on the foundation of the
first-in-class ST2 inhibitors discovered through our previous study to target the most significant prognostic
biomarker for aGVHD. The significance of the proposed research is that the aGVHD-specific small molecule
inhibitors obtained from this work will target appropriate effector T cells to increase efficacy with reduced
toxicity. Our long-term goal is to develop oral therapeutic agents with which to treat aG...

## Key facts

- **NIH application ID:** 9851918
- **Project number:** 5R01HL141432-03
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Sophie Paczesny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,311
- **Award type:** 5
- **Project period:** 2019-06-06 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851918

## Citation

> US National Institutes of Health, RePORTER application 9851918, Development of first-in-class ST2 inhibitors for treating graft-versus-host disease (5R01HL141432-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851918. Licensed CC0.

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