First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease
一流的小分子疗法可增强炎症性肠病的肠道屏障功能
基本信息
- 批准号:10251430
- 负责人:
- 金额:$ 25.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcidsAcuteAdrenal Cortex HormonesAdult Respiratory Distress SyndromeAffectAmericanAnti-Inflammatory AgentsAryl Hydrocarbon ReceptorBifidobacteriumBiologicalBiological AssayBiological SciencesBone MarrowCellsChemicalsChronicColitisDataDevelopmentDiseaseDoseDown-RegulationDrug KineticsEnzymesEpithelialEpithelial CellsErythroidExhibitsFDA approvedFunctional disorderGoalsHumanHydrolysisImmuneIndiaInflammationInflammatoryInflammatory Bowel DiseasesInstitutesIntestinal permeabilityLiverMalignant NeoplasmsMesalamineModelingMucous MembraneMusNuclearOralOral AdministrationPathogenesisPathway interactionsPatientsPermeabilityPharmaceutical ChemistryPhasePlasmaProductionProteinsPublishingRegenerative MedicineRelapseResistanceRodentScienceSeriesSmall Business Innovation Research GrantSodium Dextran SulfateSymptomsTNF geneTestingTherapeuticTight JunctionsTissue ModelToxic effectToxicity TestsTreatment EfficacyTrinitrobenzenesulfonic AcidUlcerUlcerative ColitisUniversitiesUp-Regulationanalogbaseclaudin 4clinical remissioncytokinedesigndietaryefficacy studyefficacy testingexperimental studygastrointestinal epitheliumgenetic analysishealingimprovedinfection riskintestinal epitheliumlead optimizationmacrophagemicrobialmicrobiomemouse modelnon-alcoholicoccludinpharmacokinetics and pharmacodynamicspre-clinicalpreservationproblem drinkerresponsescaffoldside effectsmall molecule therapeuticsstem cellstherapeutic targettranscription factor
项目摘要
First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease
PA-20-260, R43 Phase I SBIR
PI: Frederick M. Ausubel
Project Summary
Inflammatory Bowel Disease (IBD), which affects approximately to 3 million Americans, is characterized by
chronic relapsing inflammation and barrier dysfunction, manifested as enhanced permeability of the intestinal
epithelium caused by a breakdown of tight junction proteins between cells. Because FDA-approved IBD
therapeutics target inflammation rather than barrier dysfunction, there is a current need for an orally available,
non-toxic, non-immunosuppressive IBD therapeutic that directly enhances barrier function and blocks
progression to more severe forms of IBD. Artus Therapeutics is developing IBD therapeutics inspired by the
natural microbiome compound urolithin A (UroA). UroA exhibits anti-inflammatory activity and a highly favorable
toxicity profile in rodents and humans, but its lack of stability at low pH is a major impediment for its further
development. Artus therapeutics has synthesized a urolithin analog, ARTX-2, that is significantly more acid
stable and more resistant to hydrolysis by digestive enzymes than UroA. Published and preliminary data show
that oral administration of ARTX-2 dramatically mitigates the symptoms of dextran sodium sulphate (DSS) or
2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced ulcerative colitis in mice. Further, ARTX-2 up-regulates tight
junction proteins (TJPs) including Claudin4 and Occludin in gut epithelium as well as blocks LPS-induced
inflammatory cytokines in bone marrow derived macrophages (BMDMs). Genetic analysis in mice shows that
the bioactivity of ARTX-2 is dependent upon the aryl hydrocarbon receptor (AhR) and the nuclear transcription
factor (erythroid-derived 2)-like 2 (Nrf2). Based on these observations, it was concluded ARTX-2 mitigates IBD
through activation of AhR-dependent pathways at two distinct levels: by (i) preserving and/or enhancing gut
barrier function and (ii) reducing systemic and acute inflammation by downregulating inflammatory cytokines in
immune cells. Based on the promising data with ARTX-2, 44 more ARTX-2 analogs have been synthesized and
preliminary data show that some of these analogs appear to be more potent than ARTX-2 in blocking the
production of inflammatory cytokines in BMDMs. In this SBIR Phase I application, we propose lead optimization
of ARTX-2. In Aim 1, we will compare ARTX-2 and 44 ARTX-2 analogs with respect to: 1) upregulation of TJPs:
2) decrease in epithelial permeability; and 3) downregulation of cytokines. Up to 10 analogs that are equally or
more potent than ARTX-2 will be further tested for their efficacy in dose-response assays. In Aim 2, we will carry
out efficacy studies in the mouse TNBS chemically-induced model of ulcerative coliits for the top 5 prioritized
compounds from Aim 1. For the 3 most efficacious compounds in the mouse TNBS model, we will further test
for efficacy in the mouse DSS chemically-induced model of ulcerative colitis. The overall goal of the proposed
project is to identify 2-3 ARTX-2 analogs that are equally or more potent that ARTX-2 for advancement to a
Phase II project where further PK and toxicity testing will allow us to identify a single compound that will be
advanced into IND-enabling studies.
Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel Project Summary - Page 1 of 1
用于增强炎症性肠病肠道屏障功能的一流小分子疗法
PA-20-260,R43 I期SBIR
PI:Frederick M. Ausubel
项目摘要
炎症性肠病(IBD)影响约300万美国人,其特征在于:
慢性复发性炎症和屏障功能障碍,表现为肠道通透性增强
由细胞间紧密连接蛋白的破坏引起的上皮。因为FDA批准的IBD
治疗剂靶向炎症而不是屏障功能障碍,目前需要口服可利用的,
无毒、非免疫抑制性IBD治疗剂,其直接增强屏障功能并阻断
进展为更严重的IBD形式。Artus Therapeutics正在开发IBD疗法,其灵感来自于
天然微生物组化合物尿石素A(UroA)。UroA具有抗炎活性,
虽然其在啮齿动物和人类中的毒性概况是已知的,但其在低pH下缺乏稳定性是其进一步应用的主要障碍。
发展Artus Therapeutics已经合成了一种尿石素类似物ARTX-2,
比UroA更稳定,更耐消化酶水解。公布的数据和初步数据显示,
口服ARTX-2显著减轻葡聚糖硫酸钠(DSS)或
2,4,6-三硝基苯磺酸(TNBS)诱导小鼠溃疡性结肠炎。此外,ARTX-2上调紧密
连接蛋白(TJPs),包括肠上皮中的Claudin 4和Occludin,并阻断LPS诱导的
骨髓源性巨噬细胞(BMDM)中的炎性细胞因子。对老鼠的遗传分析表明,
ARTX-2的生物活性依赖于芳烃受体(AhR)和核转录,
因子(红细胞衍生2)样2(Nrf 2)。根据这些观察结果,得出结论,ARTX-2可缓解IBD
通过在两个不同的水平上激活AhR依赖性途径:通过(i)保护和/或增强肠道
屏障功能和(ii)通过下调炎性细胞因子减少全身性和急性炎症,
免疫细胞。基于ARTX-2的有希望的数据,已经合成了另外44种ARTX-2类似物,
初步数据显示,这些类似物中的一些似乎比ARTX-2更有效地阻断
BMDM中炎性细胞因子的产生。在这个SBIR第一阶段的应用程序中,我们提出了铅优化
ARTX-2在目标1中,我们将比较ARTX-2和44种ARTX-2类似物:1)TJP的上调:
2)上皮通透性降低;和3)细胞因子下调。多达10种类似物,
将在剂量反应测定中进一步测试比ARTX-2更有效的化合物的功效。在目标2中,我们将携带
在小鼠TNBS化学诱导的溃疡性结肠炎模型中进行的前5项优先治疗的有效性研究
目标1的化合物。对于小鼠TNBS模型中3种最有效的化合物,我们将进一步测试
在溃疡性结肠炎的小鼠DSS化学诱导模型中的功效。拟议的总体目标
项目是鉴定2-3种ARTX-2类似物,它们与ARTX-2同等或更有效地用于发展成
II期项目,进一步的PK和毒性测试将使我们能够确定一种单一的化合物,
推进IND赋能研究。
Artus Therapeutics PA-20-260 / PI:Frederick M. Ausubel项目摘要-第1页,共1页
项目成果
期刊论文数量(0)
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Frederick M Ausubel其他文献
Frederick M Ausubel的其他文献
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{{ truncateString('Frederick M Ausubel', 18)}}的其他基金
First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome (ARDS) as potential therapeutics for COVID-19
一流的小分子,可增强急性呼吸窘迫综合征 (ARDS) 期间的肺屏障功能,作为 COVID-19 的潜在疗法
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