First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease

一流的小分子疗法增强炎症性肠病的肠屏障功能 PA-20-260，R43一期丁苯橡胶 少年派：弗雷德里克·M·奥苏贝尔 项目摘要 炎症性肠病(IBD)影响着大约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 由于细胞间紧密连接蛋白的分解而形成的上皮。因为FDA批准的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、非免疫抑制的IBD治疗方法，直接增强屏障功能和阻断 进展为更严重的IBD形式。Artus Treeutics正在开发IBD疗法，灵感来自 天然微生物组化合物尿素A(Uroa)。Uroa显示出抗炎活性和高度有利的 在啮齿动物和人类中的毒性分布，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 Treateutics已经合成了一种尿锂类似物ARTX-2，它的酸性要强得多 比尿酸更稳定，更耐消化酶的水解。公布的和初步的数据显示 口服ARTX-2可显著缓解葡聚糖硫酸钠(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上调了TECH 包括Claudin4和occludin在内的连接蛋白(TJPs)在肠上皮细胞中的表达及阻断内毒素诱导的作用 骨髓来源巨噬细胞(BMDM)中的炎性细胞因子。对小鼠的遗传分析表明 ARTX-2的生物活性依赖于芳烃受体(AhR)和核转录 因子(红系衍生的2)样2(NRF2)。根据这些观察，可以得出结论：ARTX-2可以缓解IBD 通过在两个不同的水平激活AhR依赖的通路：(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的有前景的数据，又合成了44个ARTX-2类似物，并 初步数据显示，其中一些类似物似乎比ARTX-2更有效地阻断 BMDM中炎性细胞因子的产生。在此SBIR第一阶段应用中，我们提出了领先优化 ARTX-2。在目标1中，我们将从以下方面比较ARTX-2和44个ARTX-2类似物：1)上调TJP： 2)上皮通透性降低；3)细胞因子下调。最多10个相同或相同的类比 比ARTX-2更有效的药物将在剂量反应试验中进一步测试其有效性。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对排名前5位的OUT疗效研究 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 在DSS化学诱导的小鼠溃疡性结肠炎模型中的疗效。建议的总体目标是 项目是确定2-3个ARTX-2类似物，这些类似物与ARTX-2同等或更有效，可提高到 第二阶段项目，进一步的PK和毒性测试将使我们能够确定单一的化合物将是 进入支持IND的研究。 Artus Treateutics PA-20-260/PI：Frederick M.Ausubel项目摘要-第1页，共1页

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