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: 10521673
• 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/10521673
• 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; Mediating; 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; TRAF6 gene; Testing; Therapeutic; Thromboembolism; Thrombosis; Time; Transgenic Mice; Treatment Protocols; Tumor Necrosis Factor Receptor; Up-Regulation; Work; analog; base; 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; macrophage; 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.

项目摘要 尽管炎症性肠病（IBD）的治疗方面取得了进步，但许多患者未能做出反应 治疗。因此，有必要找到针对IBD的新治疗方法。 CD40-CD154途径是 针对IBD和其他炎症性疾病的已知靶标。临床试验表明CD40与 抗CD154抗体减少了炎症。但是，抗CD154抗体引起血栓形成 （与CD40的抑制无关）。此外，预计会引起全球抑制CD40的其他方法 增加机会性感染的风险。鉴定抑制CD40诱导的炎症的策略 这不会诱导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，阻止CD40和细胞内适配器蛋白之间的相互作用抑制 CD40引起的炎症反应，同时保留了对机会性病原体完整的保护。 我们鉴定了一个结合衔接蛋白，阻止CD40信号的小分子 体外炎症反应在IBD小鼠模型中减少肠道炎症。化合物 不会损害对机会性病原体的抗药性。 该化合物具有次优的溶解度和微粒体稳定性。迄今为止设计的一些类似物 显示出溶解度或微粒体稳定性方面有所提高，需要进一步优化。目标 此应用是为了开发一种将在小鼠和人类IBD系统中测试的优化抑制剂。 中心假设是具有提高溶解度和微粒稳定性的有效类似物将最佳 块CD40信号，并明显抑制IBD小鼠模型以及CD40驱动的炎症 IBD患者肠细胞的炎症反应。为了检验这一假设，我们将设计和 产生化合物的类似物，测试其性质，在报告基细胞和 肠细胞并测试IBD动物模型中的铅抑制剂。在第一个特定目的中，我们将使用结构 借助对接模型的活动关系，以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信号及其的能力 适配器蛋白的亲和力。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 在体内抑制CD40信号传导。在第三个目标中，我们将确定铅模拟是否会降低肠道 IBD小鼠模型中的炎症，并抑制CD40诱导的炎症分子在 IBD患者的肠细胞。拟议的工作可能会导致基于小说的新策略来治疗IBD 抑制CD40信号传导的方法。