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

异基因造血细胞移植(HCT)是一种潜在的血液相关癌症的治疗方法 包括白血病、淋巴瘤和多发性骨髓瘤。它的临床成功一直受到频繁的 发生严重和危及生命的急性移植物抗宿主病(AGVHD)。虽然监控 预后血浆生物标志物使临床医生能够对aGVHD发病时的高危患者进行侵袭性分层 在治疗方面，到目前为止，还没有专门针对移植物抗宿主病开发的药物，随后也没有得到批准。在这些人中 AGVHD生物标志物中，升高的可溶性刺激-2(Sst2，ST2又称IL33Rc)水平最高 预测激素耐药aGVHD导致非复发相关死亡的重要因素。Sst2，正在运行 作为一种诱饵受体，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发展中的炎性1型免疫。我们的中心假设是Sst2可以是一个 靶向治疗和阻断Sst2/IL-33相互作用是改善aGVHD的新策略。支持 假设，我们已经报道，在小鼠移植期间给予ST2中和抗体会导致 使移植后Sst2产生减少，Th2和Tregs细胞数量增加，导致 减轻aGVHD，提高存活率。在同一目标的推动下，我们最近完成了一个项目，以 通过高通量筛选和筛选发现三类小分子ST2抑制剂 计算分析。当在小鼠aGVHD模型中进行评估时，一种化合物产生的结果最好 包括提高存活率，降低血浆Sst2水平，以及移植物抗白血病作用不减。 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 发展，包括发展到口服生物利用剂，不可行的抗体为基础的治疗。 在本研究中，三个具体目标是：1)在一个引线的基础上设计和合成新的类似物 化合物，目的是提高其效力、选择性和用于体内研究的物理化学性质。 2)在体外aGVHD实验中测定抑制剂的体外稳定性/毒性及其活性。3) 体内吸收、分布、代谢和排泄(ADME)/毒性的评估 它们在移植物抗宿主病小鼠模型中的效果。目前的aGVHD治疗采用的是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 通过我们先前的研究发现的第一类ST2抑制剂，用于靶向最显著的预后 移植物抗宿主病的生物标志物。这项研究的意义在于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，以提高疗效并降低 毒性。我们的长期目标是开发治疗aGVHD和其他疾病的口服治疗剂 ST2/IL-33轴介导的疾病。

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.