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）是治疗血液相关癌症的潜在疗法包括白血病、淋巴瘤和多发性骨髓瘤。其临床成功受到频繁的严重且危及生命的急性移植物抗宿主病（aGVHD）的发展。虽然监测预后血浆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，以识别侵袭性治疗方面，迄今为止还没有专门针对 aGVHD 开发并随后获得批准的药物。其中 aGVHD 生物标志物中，可溶性 STimulation-2（sST2，ST2 也称为 IL33Rc）水平升高最为明显。预测导致非复发相关死亡的类固醇抗性 aGVHD 的重要因素。 sST2，功能正常作为诱饵受体，捕获 IL-33 以减少 2 型细胞因子的分泌，并有助于明显的促- aGVHD 发展中的 1 型炎症免疫。我们的中心假设是 sST2 可以是治疗靶点和阻断 sST2/IL-33 相互作用是改善 aGVHD 的新策略。支持根据这一假设，我们报道了在小鼠中移植前给予 ST2 中和抗体会导致移植后 sST2 产量减少以及 Th2 和 Tregs 细胞数量增加减轻 aGVHD 并提高生存率。在同一目标的推动下，我们最近完成了一个项目通过高通量筛选和发现三种化学类别的小分子 ST2 抑制剂计算分析。在小鼠 aGVHD 模型中进行评估时，一种化合物可产生最佳结果包括提高生存率、降低血浆 sST2 水平以及不减弱的移植物抗白血病效应。这项研究的基本原理是我们的先导化合物可以进一步优化用于临床前治疗开发，包括开发口服生物可利用的药物，这对于基于抗体的治疗是不可行的。在这项研究中，三个具体目标是：1）基于一个先导物设计和合成新的类似物化合物，旨在提高其在体内研究中的效力、选择性和理化性质。 2) 体外aGVHD测定中抑制剂的体外稳定性/毒性及其活性的测定。 3）评估抑制剂和药物的体内吸收、分布、代谢和排泄 (ADME)/毒性它们在 aGVHD 小鼠模型中的功效。目前的aGVHD疗法采用针对其他疾病设计的药物这些药物针对的是非特异性效应 T 细胞。我们的创新方法建立在我们之前的研究发现了一流的 ST2 抑制剂，可针对最重要的预后 aGVHD 的生物标志物。本研究的意义在于，aGVHD 特异性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，以减少毒性。我们的长期目标是开发口服治疗剂来治疗 aGVHD 和其他疾病 ST2/IL-33 轴介导的疾病。