From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

Abstract

Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression

“…We would instead postulate that modulating the phenotype of the macrophage within the glioma environment per se might warrant a more precision-based approach, a strategy consistent with our study using amphotericin B to reprogram the brain tumor environment 39 . While there are therapeutic strategies emerging to sequester secreted IL-33 using soluble ST2 receptors 142 , our data provides the provocative notion that targeting nuclear accumulation of IL-33 exclusively may have therapeutic benefit by maintaining a tumor environment with TAMs of a tumor-suppressive phenotype. In addition, as suggested by Quail and Joyce, the tumor microenvironment can be further modified during the course of treatment, and thus should be taken into consideration when examining responders and nonresponders to a specific therapeutic regimen 16 .…”

Biomarkers for Allogeneic HCT Outcomes

“…In rheumatologic diseases, cytokines have been identified as markers and targeted with Janus Kinase (JAK) inhibitors either directly or via intracellular signaling (108). This is also the case in cancer, where signal transducer and activation of transcription 3 (STAT3) is a great potential therapeutic candidate that has been targeted using a small-molecule degrader for complete tumor regression (109). Similar drug targetable biomarkers in GVHD would be very beneficial as these would target the specific biomarker to reduce GVHD, promote therapy, and lower toxicity.…”

Clinical Proteomics for Post‐Hematopoeitic Stem Cell Transplantation Outcomes

“…Targeting the extracellular domain (or ectodomain, ECD) with antibodies or biologics are proven therapeutic strategies and include anakinra for IL1R and two ST2 antibody‐based therapies, RG6149/AMG282 and GSK3772847, currently in phase 2 clinical trials . Furthermore, small molecule ST2 inhibitors were discovered through a combination of high throughput screening, small angle X‐ray scattering (SAXS) exploration, and computational analysis and proven active in vivo in two different aGVHD models . Of note, ectodomains of cytokine receptors are challenging drug targets and no small molecule inhibitor has yet been reported to exhibit activity in vivo .…”

“…The success of preemption must include a reduction not only in the incidence of aGVHD, but also in infectious complications and relapse. Future studies will be the establishment of clinical trials using both biomarkers for risk stratification and GVHD‐specific drugs (as has been shown for ST2 in murine models) for treatment in high‐risk populations.…”