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:10093120
- 负责人:
- 金额:$ 63.61万
- 依托单位:
- 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 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Graft Versus Host DiseaseAdoptedAllogenicAnimal ModelAntibodiesAntibody TherapyAttenuatedBioavailableBiological AssayBiological AvailabilityBiological MarkersBloodCellsCessation of lifeChemicalsClinicalComputer AnalysisComputer ModelsCrystallizationCytotoxic T-LymphocytesDataDevelopmentDiseaseDisease modelDrug DesignDrug EvaluationDrug KineticsDrug TargetingEndothelial CellsExcretory functionExhibitsFoundationsGenesGoalsHeart failureHelper-Inducer T-LymphocyteHematopoieticHumanImmune responseImmunityIn VitroInflammatoryInflammatory Bowel DiseasesInterleukin-1 ReceptorsInterleukin-13Interleukin-4Interleukin-5Interleukin-9InvestigationJAK1 geneLeadLifeLigandsLigationLymphoid CellMalignant NeoplasmsMaximum Tolerated DoseMeasuresMediatingMembraneMetabolicMetabolismMixed Lymphocyte Culture TestMonitorMorbidity - disease rateMultiple MyelomaMusNamesOralOrganOutcomePathologicPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPharmacologyPlasmaPreclinical Drug DevelopmentProductionPrognostic MarkerPropertyProtein IsoformsProteinsRefractoryRegulatory T-LymphocyteReportingResearchSeriesSerumSpottingsSteroid ResistanceSteroidsStromal CellsStructureStudy modelsT-Cell ProliferationT-Lymphocyte SubsetsTh2 CellsTherapeuticTherapeutic AgentsToxic effectUlcerative ColitisWorkabsorptionaggressive therapyallograft rejectionanalogbaseburden of illnesscost effectivecurative treatmentscytokinedesigndrug developmenteffector T cellexperimental studygraft vs host diseasegraft vs leukemia effectheart allografthematopoietic cell transplantationhigh riskhigh throughput screeningimprovedin vitro Assayin vivoinhibitor/antagonistinnovationleukemia/lymphomamast cellmortalitymouse modelneutralizing antibodynovel strategiespost-transplantpre-clinicalprognosticprophylacticreceptorscaffoldsmall moleculesmall molecule inhibitorsuccesstherapeutic developmenttherapeutic targettherapy 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.
异基因造血干细胞移植(HCT)是治疗血液相关肿瘤的一种有效方法
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
严重和危及生命的急性移植物抗宿主病(aGVHD)的发展。虽然监测
预后性血浆生物标志物使临床医生能够在aGVHD发作时对高风险患者进行分层,
然而,迄今为止,还没有专门针对aGVHD开发并随后获得批准的药物。中
在aGVHD生物标志物中,可溶性STimulation-2(sST 2,ST 2也称为IL33Rc)的水平升高是最常见的。
预测导致非复发相关死亡的类固醇耐药aGVHD的重要因素。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,并有助于明显的促细胞增殖,
aGVHD发展中的炎性1型免疫。我们的中心假设是sST2可以是一种
治疗靶点和阻断sST 2/IL-33相互作用是改善aGVHD的新策略。支持
假设,我们已经报道了在小鼠中的ST 2中和抗体的腹膜移植给药导致
移植后sST 2产生减少,Th2和TcB细胞数量增加,
减轻aGVHD并提高存活率。基于同样的目标,我们最近完成了一个项目,
通过采用高通量筛选发现三种化学类别的小分子ST2抑制剂,
计算分析当在小鼠aGVHD模型中进行评估时,一种化合物产生最佳结果
包括存活率提高、血浆sST 2水平降低和移植物抗白血病效应未减弱。
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,包括口服生物可利用剂的进展,对于基于抗体的治疗剂是不可行的。
本研究的三个具体目标是:1)设计合成基于一个先导化合物的新类似物
化合物,目的是改善其效力、选择性和物理化学性质用于体内研究。
2)抑制剂的体外稳定性/毒性及其在体外aGVHD测定中的活性的测定。第三章
评估抑制剂的体内吸收、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治疗采用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,
aGVHD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,以增加功效,
毒性我们的长期目标是开发用于治疗aGVHD和其他移植物抗宿主病的口服治疗剂。
ST2/IL-33轴介导的疾病。
项目成果
期刊论文数量(0)
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Sophie Paczesny其他文献
Sophie Paczesny的其他文献
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{{ truncateString('Sophie Paczesny', 18)}}的其他基金
Chronic Graft-Versus-Host Disease Biomarkers: Prediction of Resistance to Therapy
慢性移植物抗宿主病生物标志物:治疗耐药性的预测
- 批准号:
10751970 - 财政年份:2023
- 资助金额:
$ 63.61万 - 项目类别:
IL-33 induced-lL-9 producing type 2 innate lymphoid cells in the regulation of acute lung injury after hematopoietic stem cell transplantation (HSCT) in pediatric patients
IL-33诱导产生IL-9的2型先天淋巴细胞在调节儿科患者造血干细胞移植(HSCT)后急性肺损伤中的作用
- 批准号:
10540768 - 财政年份:2022
- 资助金额:
$ 63.61万 - 项目类别:
IL-33 induced-lL-9 producing type 2 innate lymphoid cells in the regulation of acute lung injury after hematopoietic stem cell transplantation (HSCT) in pediatric patients
IL-33诱导产生IL-9的2型先天淋巴细胞在儿科患者造血干细胞移植(HSCT)后急性肺损伤的调节中
- 批准号:
10392134 - 财政年份:2022
- 资助金额:
$ 63.61万 - 项目类别:
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
- 批准号:
10357753 - 财政年份:2019
- 资助金额:
$ 63.61万 - 项目类别:
Biomarkers for risk of chronic Graft-Versus-Host Disease occurrence
慢性移植物抗宿主病发生风险的生物标志物
- 批准号:
9433011 - 财政年份:2017
- 资助金额:
$ 63.61万 - 项目类别:
Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease
转化新型药物靶向生物标志物来治疗移植物抗宿主病
- 批准号:
8501916 - 财政年份:2013
- 资助金额:
$ 63.61万 - 项目类别:
High Throughput Screening (HTS) to Discover Graft-Versus-Host Disease Inhibitors
高通量筛选 (HTS) 发现移植物抗宿主疾病抑制剂
- 批准号:
8474927 - 财政年份:2013
- 资助金额:
$ 63.61万 - 项目类别:
High Throughput Screening (HTS) to Discover Graft-Versus-Host Disease Inhibitors
高通量筛选 (HTS) 发现移植物抗宿主疾病抑制剂
- 批准号:
8649031 - 财政年份:2013
- 资助金额:
$ 63.61万 - 项目类别:
Bridging Pediatric and Adult Biomarkers of Graft-Versus-Host-Disease
桥接儿童和成人移植物抗宿主疾病的生物标志物
- 批准号:
8842670 - 财政年份:2013
- 资助金额:
$ 63.61万 - 项目类别:
Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease
转化新型药物靶向生物标志物来治疗移植物抗宿主病
- 批准号:
8841692 - 财政年份:2013
- 资助金额:
$ 63.61万 - 项目类别:
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