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

开发用于治疗移植物抗宿主病的一流 ST2 抑制剂

基本信息

批准号：
10357753
负责人：
Sophie Paczesny
金额：
$ 63.37万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-06 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357753
关键词：
Acute Acute Graft Versus Host Disease Adopted Allogenic Animal Model Antibodies Antibody Therapy Attenuated Biological Assay Biological Availability Biological Markers Blood Cells Cessation of life Chemicals Clinical Computer Analysis Computer Models Crystallization Cytotoxic T-Lymphocytes Data Development Disease Disease model Drug Design Drug Evaluation Drug Kinetics Drug Targeting Endothelial Cells Excretory function Exhibits Foundations Genes Goals Heart failure Helper-Inducer T-Lymphocyte Hematopoietic Human Immune response Immunity In Vitro Inflammatory Inflammatory Bowel Diseases Interleukin-1 Receptors Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-9 Investigation JAK1 gene Lead Life Ligands Ligation Lymphoid Cell Malignant Neoplasms Maximum Tolerated Dose Measures Mediating Membrane Metabolic Metabolism Mixed Lymphocyte Culture Test Monitor Morbidity - disease rate Multiple Myeloma Mus Names Oral Organ Outcome Pathologic Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacology Plasma Preclinical Drug Development Production Prognostic Marker Property Protein Isoforms Proteins Refractory Regulatory T-Lymphocyte Reporting Research Series Serum Spottings Steroid Resistance Steroids Stromal Cells Structure Study models T-Cell Proliferation T-Lymphocyte Subsets Th2 Cells Therapeutic Therapeutic Agents Toxic effect Ulcerative Colitis Work absorption aggressive therapy allograft rejection analog base burden of illness cost effective curative treatments cytokine design drug development effector T cell experimental study graft vs host disease graft vs leukemia effect heart allograft hematopoietic cell transplantation high risk high throughput screening improved in vitro Assay in vivo inhibitor innovation leukemia/lymphoma mast cell mortality mouse model neutralizing antibody novel strategies post-transplant pre-clinical prognostic prophylactic receptor scaffold small molecule small molecule inhibitor success therapeutic development therapeutic target therapy outcome

项目摘要

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 aGVHD and other ST2/IL-33 axis mediated diseases.

同种异体造血细胞移植（HCT）是一种针对血液相关癌症的治疗疗法包括白血病，淋巴瘤和多发性骨髓瘤。它的临床成功受到了频繁的限制发生严重和威胁生命的急性移植与宿主疾病（AGVHD）的发展。虽然监视预后等离子体生物标志物使临床医生能够在AGVHD发作时对高危患者进行分层治疗，没有专门针对AGVHD开发的药物，随后迄今已批准。在 AGVHD生物标志物，可溶性刺激水平升高（SST2，ST2也称为IL33RC）是最多的预测抗类固醇AGVHD的重要因素，这会导致非透明质量相关的死亡。 SST2，功能作为诱饵受体，捕获IL-33以减少2型细胞因子的分泌，并有助于公开促进 AGVHD开发中的炎症1型免疫力。我们的中心假设是SST2可以是 SST2/IL-33相互作用的治疗靶标和阻滞是改善AGVHD的一种新型策略。支持假设，我们报道了小鼠铅的植物内植物植入术中和中和抗体减少SST2的产生和TH2和Tregs细胞的数量增加，导致缓解了AGVHD并改善了生存。以同一目标的激励，我们最近完成了一个项目通过使用高吞吐量筛选和计算分析。当在鼠标AGVHD模型中评估时，一种化合物会产生最佳结果包括提高的生存率，SST2的血浆水平降低和未减少的移植物 - 对抗血症效应。这项研究的理由是，我们的铅化合物可以进一步优化用于临床前治疗开发，包括对口服生物利用剂的进步，对于基于抗体的治疗剂而言是不可行的。在这项研究中，三个具体目标是：1）根据一个铅设计和合成新的类似物化合物的目的是提高体内研究的效力，选择性和物理化学特性。 2）确定抑制剂的体外稳定性/毒性及其在体外AGVHD测定中的活性。 3）评估体内吸收，分布，代谢和排泄（ADME）/抑制剂和毒性它们在AGVHD小鼠模型中的功效。当前的AGVHD疗法采用专为其他疾病设计的药物这些药物靶向非特异性效应T细胞。我们的创新方法建立在通过我们先前的研究发现的第一类ST2抑制剂，以瞄准最重要的预后 AGVHD的生物标志物。拟议的研究的重要性是AGVHD特异性的小分子从这项工作中获得的抑制剂将靶向适当的效应T细胞，以提高功效毒性。我们的长期目标是开发口服治疗剂来治疗AGVHD和其他 ST2/IL-33轴介导的疾病。