Small molecule inhibitor of CD40 signaling for the control of inflammatory bowel disease

用于控制炎症性肠病的 CD40 信号小分子抑制剂

• 批准号: 10673011
• 负责人: CARLOS S SUBAUSTE
• 金额: $ 35.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673011
• 关键词: Adaptor Signaling Protein; Affinity; Animal Model; Anti-CD40; Antibodies; Binding; Biological Assay; Blocking Antibodies; Blood Platelets; Cell Adhesion Molecules; Cells; Clinical Trials; Colitis; Collaborations; Dendritic Cells; Disease; Docking; Dose; Endothelial Cells; Endothelium; Epithelial Cells; Gastrointestinal tract structure; Genetic; Histopathology; Human; Ileitis; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intercellular adhesion molecule 1; Intestinal Diseases; Intestines; Knowledge; Lead; Leukocytes; Luciferases; MAPK1 gene; MAPK11 gene; MAPK8 gene; Macrophage; Mediating; Medicine; Microsomes; Modeling; Monoclonal Antibodies; Mus; OX40; Opportunistic Infections; Oral; Pathway interactions; Patients; Permeability; Phosphorylation; Predisposition; Property; RPS6KA5 gene; Receptor Signaling; Reporter; Resistance; Risk; Series; Signal Transduction; Solubility; Structure-Activity Relationship; System; T-Lymphocyte; TNF receptor-associated factor 3; TNFRSF1A gene; TNFRSF5 gene; TNFRSF8 gene; TNFSF5 gene; TRADD gene; TRAF2 gene; Testing; Therapeutic; Thromboembolism; Thrombosis; Transgenic Mice; Treatment Protocols; Tumor Necrosis Factor Receptor; Up-Regulation; Work; analog; chemokine; crosslink; cytokine; design; dextran sulfate sodium induced colitis; effective therapy; experience; gut inflammation; high throughput screening; improved; in vivo; inhibitor; lead optimization; lymphotoxin beta receptor; monocyte; mouse model; murine colitis; neutrophil; novel; novel strategies; novel therapeutic intervention; opportunistic pathogen; prevent; programs; recruit; response; side effect; small molecule; small molecule inhibitor; treatment response

PROJECT SUMMARY Despite advances in the treatment of inflammatory bowel disease (IBD), many patients fail to respond to therapy. Thus, there is a need to find new therapeutic approaches against IBD. The CD40-CD154 pathway is a known target against IBD and other inflammatory disorders. Clinical trials indicated that CD40 blockade with anti-CD154 antibodies reduced inflammation. However, the anti-CD154 antibodies caused thrombosis (unrelated to inhibition of CD40). Moreover, other approaches to cause global inhibition of CD40 are predicted to increase the risk of opportunistic infections. Identification of a strategy to inhibit CD40-induced inflammation that does not induce thrombosis or opportunistic infections can be a major advance in the treatment of IBD. We uncovered that blocking the interaction between CD40 and an intracellular adaptor protein inhibits pro- inflammatory responses induced by CD40 while leaving protection against an opportunistic pathogen intact. We identified a small molecule that binds the adaptor protein, blocks CD40 signaling, reduces pro- inflammatory responses in vitro and diminishes intestinal inflammation in mouse models of IBD. The compound did not impair resistance against an opportunistic pathogen. The compound has suboptimal solubility and microsomal stability. While some analogs designed to date showed some improvement in solubility or microsomal stability, further optimization is necessary. The objective of this application is to develop an optimized inhibitor that will be tested in mouse and human IBD systems. The central hypothesis is that a potent analog with improved solubility and microsomal stability will optimally block CD40 signaling, and markedly suppress inflammation in mouse models of IBD as well as CD40-driven inflammatory responses in intestinal cells from patients with IBD. To test this hypothesis, we will design and generate analogs of the compound, test their properties, perform signaling studies in reporter cells and intestinal cells and test the lead inhibitor in animal models of IBD. In the first specific aim we will use structure activity relationships with the aid of a docking model to design and generate analogs of the compound in order to improve solubility and microsomal stability. We will examine their ability to inhibit CD40 signaling and their affinity for the adaptor protein. In the second aim, we will test the most potent analogs to determine if they inhibit CD40 signaling in vivo. In the third aim, we will determine if the lead analog reduces intestinal inflammation in mouse models of IBD and inhibits CD40-induced expression of inflammatory molecules in intestinal cells from IBD patients. The proposed work may lead to a new strategy to treat IBD based on a novel approach to inhibit CD40 signaling.

项目概要 尽管炎症性肠病（IBD）的治疗取得了进展，但许多患者对治疗没有反应 治疗。因此，需要寻找针对IBD的新治疗方法。 CD40-CD154 途径是 对抗 IBD 和其他炎症性疾病的已知靶标。临床试验表明 CD40 阻断 抗 CD154 抗体可减轻炎症。然而，抗CD154抗体引起血栓形成 （与 CD40 的抑制无关）。此外，预计还有其他方法可引起 CD40 的整体抑制 增加机会性感染的风险。抑制 CD40 诱导炎症的策略的鉴定 不引起血栓形成或机会性感染可能是 IBD 治疗的重大进步。 我们发现阻断 CD40 和细胞内衔接蛋白之间的相互作用会抑制 pro- CD40 诱导的炎症反应，同时保持对机会性病原体的完整保护。 我们鉴定了一种小分子，它可以结合衔接蛋白、阻断 CD40 信号传导、减少 pro- 体外炎症反应并减少 IBD 小鼠模型的肠道炎症。该化合物 不会削弱对机会性病原体的抵抗力。 该化合物的溶解度和微粒体稳定性不佳。虽然迄今为止设计的一些类似物 显示溶解度或微粒体稳定性有所改善，需要进一步优化。目标 该应用的目的是开发一种优化的抑制剂，并将在小鼠和人类 IBD 系统中进行测试。 中心假设是，具有改善的溶解度和微粒体稳定性的有效类似物将最佳地 阻断 CD40 信号传导，并显着抑制 IBD 以及 CD40 驱动的小鼠模型中的炎症 IBD 患者肠道细胞的炎症反应。为了检验这个假设，我们将设计并 生成化合物的类似物，测试其特性，在报告细胞中进行信号传导研究， 肠细胞并在 IBD 动物模型中测试先导抑制剂。在第一个具体目标中，我们将使用结构 借助对接模型确定活性关系，以便按顺序设计和生成化合物的类似物 提高溶解度和微粒体稳定性。我们将检查它们抑制 CD40 信号传导的能力及其 对接头蛋白的亲和力。在第二个目标中，我们将测试最有效的类似物，以确定它们是否 抑制体内 CD40 信号传导。在第三个目标中，我们将确定铅类似物是否会减少肠道 IBD 小鼠模型中的炎症并抑制 CD40 诱导的炎症分子表达 来自IBD患者的肠细胞。拟议的工作可能会导致基于一种新的治疗 IBD 的新策略 抑制CD40信号传导的方法。