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

• 批准号: 10251430
• 负责人: Frederick M Ausubel
• 金额: $ 25.12万
• 依托单位: ARTUS THERAPEUTICS INC
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10251430
• 关键词: 3-Dimensional; Acids; Acute; Adrenal Cortex Hormones; Adult Respiratory Distress Syndrome; Affect; American; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Bifidobacterium; Biological; Biological Assay; Biological Sciences; Bone Marrow; Cells; Chemicals; Chronic; Colitis; Data; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Enzymes; Epithelial; Epithelial Cells; Erythroid; Exhibits; FDA approved; Functional disorder; Goals; Human; Hydrolysis; Immune; India; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Institutes; Intestinal permeability; Liver; Malignant Neoplasms; Mesalamine; Modeling; Mucous Membrane; Mus; Nuclear; Oral; Oral Administration; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Phase; Plasma; Production; Proteins; Publishing; Regenerative Medicine; Relapse; Resistance; Rodent; Science; Series; Small Business Innovation Research Grant; Sodium Dextran Sulfate; Symptoms; TNF gene; Testing; Therapeutic; Tight Junctions; Tissue Model; Toxic effect; Toxicity Tests; Treatment Efficacy; Trinitrobenzenesulfonic Acid; Ulcer; Ulcerative Colitis; Universities; Up-Regulation; analog; base; claudin 4; clinical remission; cytokine; design; dietary; efficacy study; efficacy testing; experimental study; gastrointestinal epithelium; genetic analysis; healing; improved; infection risk; intestinal epithelium; lead optimization; macrophage; microbial; microbiome; mouse model; non-alcoholic; occludin; pharmacokinetics and pharmacodynamics; pre-clinical; preservation; problem drinker; response; scaffold; side effect; small molecule therapeutics; stem cells; therapeutic target; transcription factor

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

第一类小分子疗法以增强炎症性肠病的肠道屏障功能 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，其特征是 慢性复发炎症和障碍功能障碍，表现为肠道的渗透性增强 细胞之间紧密连接蛋白的分解引起的上皮。因为FDA批准的IBD 治疗剂靶向炎症，而不是障碍功能障碍，目前需要口服可用， 无毒的非免疫抑制性IBD治疗性，可直接增强屏障功能和阻塞 进展为更严重的IBD。 Artus Therapeutics正在开发受IBD治疗剂的启发 天然微生物组复合尿素A（UROA）。 UROA表现出抗炎活性和高度有利的 啮齿动物和人类的毒性特征，但在低pH值下缺乏稳定性是其进一步的主要障碍 发展。 Artus Therapeutics已合成了尿石类似物ARTX-2，它明显更多 与UROA相比，消化酶对水解的稳定，对水解具有更大的抵抗力。发布和初步数据显示 ARTX-2的口服给药可极大地减轻葡萄糖硫酸钠（DSS）或 2,4,6-三硝基苯甲酸（TNB）诱导小鼠溃疡性结肠炎。此外，ARTX-2上调紧密 连接蛋白（TJP），包括肠道上皮中的claudin4和occludin，以及阻止LPS诱导的 骨髓衍生的巨噬细胞（BMDMS）中的炎症细胞因子。小鼠的遗传分析表明 ARTX-2的生物活性取决于芳基烃受体（AHR）和核转录 因子（红细胞来源2） - 类似2（NRF2）。基于这些观察结果，得出结论ARTX-2减轻IBD 通过激活AHR依赖性途径在两个不同的层面上：通过（i）保存和/或增强肠道 屏障功能以及（ii）通过下调炎症细胞因子来减少全身性和急性炎症 免疫细胞。基于ARTX-2的有前途的数据，已合成了44个ARTX-2类似物，并且 初步数据表明，其中一些类似物似乎比ARTX-2更有效 BMDMS中炎性细胞因子的产生。在此SBIR I期应用程序中，我们提出了铅优化 Artx-2。在AIM 1中，我们将比较ARTX-2和44 ARTX-2类似物相对于以下方面的类似：1）TJP的上调： 2）上皮渗透性的降低； 3）细胞因子的下调。最多10个类似物，或 与ARTX-2相比，将进一步测试其在剂量反应测定中的功效。在AIM 2中，我们将携带 在小鼠TNB中的效果研究化学诱导的溃疡性大肠模型的前5个优先级 AIM 1的化合物。对于鼠标TNBS模型中的3种最有效的化合物，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功效。拟议的总体目标 项目是要识别2-3个ARTX-2类似物，这些类似物与ARTX-2相同或更有效 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的化合物 发展为辅助研究。 Artus Therapeutics PA-20-260 / PI：Frederick M. Ausubel项目摘要 - 第1页，共1页