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
一流的小分子疗法可增强炎症性肠病的肠道屏障功能
PA-20-260,R43 I 期 SBIR
PI:弗雷德里克·M·奥苏贝尔
项目概要
炎症性肠病 (IBD) 影响大约 300 万美国人,其特点是
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分解引起的上皮细胞。因为 FDA 批准了 IBD
治疗的目标是炎症而不是屏障功能障碍,目前需要一种口服的、
无毒、非免疫抑制性 IBD 治疗,可直接增强屏障功能并阻断
进展为更严重的 IBD。 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 具有抗炎活性和非常有利的作用
啮齿动物和人类的毒性特征,但其在低pH值下缺乏稳定性是其进一步发展的主要障碍
发展。 Artus Therapeutics 合成了一种尿石素类似物 ARTX-2,其酸性显着增强
比 UroA 更稳定且更能抵抗消化酶的水解。已公布和初步数据显示
口服 ARTX-2 可显着减轻右旋糖酐硫酸钠 (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 上调严格
肠上皮中的连接蛋白 (TJP) 包括 Claudin4 和 Occludin,并阻断 LPS 诱导的
骨髓源性巨噬细胞 (BMDM) 中的炎症细胞因子。小鼠遗传分析表明
ARTX-2 的生物活性取决于芳烃受体 (AhR) 和核转录
因子(红细胞衍生 2)样 2 (Nrf2)。基于这些观察,得出的结论是 ARTX-2 可以减轻 IBD
通过在两个不同水平激活 AhR 依赖性途径:(i) 保护和/或增强肠道
屏障功能和(ii)通过下调炎症细胞因子来减少全身和急性炎症
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 类似物并
初步数据表明,其中一些类似物似乎比 ARTX-2 更有效地阻断
BMDM 中炎症细胞因子的产生。在此 SBIR 第一阶段应用中,我们提出了先导化合物优化
ARTX-2的。在目标 1 中,我们将在以下方面比较 ARTX-2 和 44 ARTX-2 类似物:1) TJP 的上调:
2)上皮通透性降低; 3)细胞因子的下调。最多 10 个同等或相同的类似物
比 ARTX-2 更有效的药物将在剂量反应测定中进一步测试其功效。在目标 2 中,我们将携带
小鼠 TNBS 化学诱导溃疡性结肠炎模型中针对前 5 名优先事项的疗效研究
来自Aim 1的化合物。对于小鼠TNBS模型中最有效的3种化合物,我们将进一步测试
用于小鼠 DSS 化学诱导的溃疡性结肠炎模型的疗效。拟议的总体目标
该项目的目的是鉴定 2-3 个与 ARTX-2 同等或更有效的 ARTX-2 类似物,从而将其提升为
第二阶段项目,进一步的 PK 和毒性测试将使我们能够识别出一种单一化合物
进入 IND 支持研究。
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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Frederick M Ausubel其他文献
Frederick M Ausubel的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 批准号:
10254996 - 财政年份:2021
- 资助金额:
$ 25.12万 - 项目类别:
Discovering Novel Therapeutics for Myotonic Dystrophy Type 1 (DM1)
发现 1 型强直性肌营养不良 (DM1) 的新疗法
- 批准号:
9409067 - 财政年份:2017
- 资助金额:
$ 25.12万 - 项目类别:
Identifying novel anti-infectives by high through-put screening in whole animals
通过对整体动物进行高通量筛选来鉴定新型抗感染药物
- 批准号:
7764005 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
Identifying novel anti-infectives by high through-put screening in whole animals
通过对整体动物进行高通量筛选来鉴定新型抗感染药物
- 批准号:
8126254 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
Identifying novel anti-infectives by high through-put screening in whole animals
通过对整体动物进行高通量筛选来鉴定新型抗感染药物
- 批准号:
8312372 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
Identifying novel anti-infectives by high through-put screening in whole animals
通过对整体动物进行高通量筛选来鉴定新型抗感染药物
- 批准号:
7939581 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
Identifying novel anti-infectives by high through-put screening in whole animals
通过对整体动物进行高通量筛选来鉴定新型抗感染药物
- 批准号:
8520165 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
相似国自然基金
具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
- 批准号:22007039
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
- 批准号:
- 批准年份:2019
- 资助金额:10.0 万元
- 项目类别:省市级项目
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
- 批准号:21372217
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
- 批准号:21172061
- 批准年份:2011
- 资助金额:30.0 万元
- 项目类别:面上项目
钛及含钛Lewis acids促臭氧/过氧化氢体系氧化性能的广普性、高效性及其机制
- 批准号:21176225
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于Zip Nucleic Acids引物对高度降解和低拷贝DNA检材的STR分型研究
- 批准号:81072511
- 批准年份:2010
- 资助金额:31.0 万元
- 项目类别:面上项目
海洋天然产物Makaluvic acids 的全合成及其对南海鱼虱存活的影响
- 批准号:30660215
- 批准年份:2006
- 资助金额:21.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Gene expression regulation in recurrent paediatric acute myeloid leukaemia by characterization of non-coding ribonucleic acids
通过非编码核糖核酸的表征研究复发性小儿急性髓性白血病的基因表达调控
- 批准号:
449784 - 财政年份:2020
- 资助金额:
$ 25.12万 - 项目类别:
Studentship Programs
Study of metabolism of sulfur-containing amino acids as anti-oxidant against the acute exacerbation of interstitial pneumonia
含硫氨基酸抗氧化代谢对间质性肺炎急性加重的研究
- 批准号:
16K19984 - 财政年份:2016
- 资助金额:
$ 25.12万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Omega 3 Fatty Acids Acute Neuroprotection via Mitochondria
Omega 3 脂肪酸通过线粒体提供急性神经保护作用
- 批准号:
9450547 - 财政年份:2015
- 资助金额:
$ 25.12万 - 项目类别:
Omega 3 fatty acids, acute neuroprotection via mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10447712 - 财政年份:2015
- 资助金额:
$ 25.12万 - 项目类别:
Omega 3 fatty acids, acute neuroprotection via mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10297604 - 财政年份:2015
- 资助金额:
$ 25.12万 - 项目类别:
Omega 3 Fatty Acids, Acute Neuroprotection Via Mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10655664 - 财政年份:2015
- 资助金额:
$ 25.12万 - 项目类别:
Omega 3 Fatty Acids Acute Neuroprotection via Mitochondria
Omega 3 脂肪酸通过线粒体提供急性神经保护作用
- 批准号:
8996605 - 财政年份:2015
- 资助金额:
$ 25.12万 - 项目类别:
ACUTE EFFECTS OF OLANZAPINE ON PLASMA LEPTIN, GLUCOSE TOLERANCE FREE FATTY ACIDS
奥氮平对血浆瘦素、无葡萄糖耐量脂肪酸的急性影响
- 批准号:
7951282 - 财政年份:2009
- 资助金额:
$ 25.12万 - 项目类别:
SENSITIVITY TO ACUTE INSULIN MEDIATED SUPPRESSION OF PLASMA FREE FATTY ACIDS
对胰岛素介导的血浆游离脂肪酸急性抑制的敏感性
- 批准号:
7180051 - 财政年份:2005
- 资助金额:
$ 25.12万 - 项目类别:
SENSITIVITY TO ACUTE INSULIN MEDIATED SUPPRESSION OF PLASMA FREE FATTY ACIDS
对胰岛素介导的血浆游离脂肪酸急性抑制的敏感性
- 批准号:
6977013 - 财政年份:2003
- 资助金额:
$ 25.12万 - 项目类别:














{{item.name}}会员




