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.

项目总结 尽管炎症性肠病(IBD)的治疗取得了进展，但许多患者对 心理治疗。因此，有必要寻找新的治疗方法来治疗IBD。CD40-CD154途径是一种 已知的针对IBD和其他炎症性疾病的靶点。临床试验表明，CD40阻断与 抗CD154抗体可减轻炎症。然而，抗CD154抗体导致了血栓形成 (与抑制CD40无关)。此外，还预测了导致CD40全局抑制的其他方法 以增加机会性感染的风险。确定一种抑制CD40诱导的炎症的策略 这不会导致血栓形成或机会性感染，这可能是IBD治疗的一大进步。 我们发现，阻断CD40和细胞内适配子蛋白之间的相互作用会抑制前... CD40诱导的炎症反应，同时对机会性病原体的保护完好无损。 我们发现了一种小分子，它能结合接头蛋白，阻断CD40信号，减少前... 体外炎症反应和减轻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。 该化合物具有次佳的溶解度和微球稳定性。虽然到目前为止设计的一些类似物 在溶解度或微球稳定性方面有所改善，有待进一步优化。目标是 这一应用的目的是开发一种优化的抑制剂，将在小鼠和人类IBD系统中进行测试。 中心假设是，一种具有更好的溶解性和微粒体稳定性的强效类似物将是最佳的 阻断CD40信号，并显著抑制IBD小鼠模型的炎症以及CD40驱动的炎症 炎症性肠病患者肠道细胞的炎症反应。为了验证这一假设，我们将设计和 产生化合物的类似物，测试它们的性质，在报告细胞中进行信号研究，以及 并在IBD动物模型中检测铅抑制物。在第一个具体目标中，我们将使用结构 借助对接模型设计和生成化合物的类似物的活性关系 以提高溶解度和微粒体稳定性。我们将研究它们抑制CD40信号的能力以及它们的 对接头蛋白的亲和力。在第二个目标中，我们将测试最强大的类似物以确定它们是否 体内抑制CD40信号转导。在第三个目标中，我们将确定铅类似物是否减少肠道 炎性反应抑制CD40诱导的炎性分子在IBD小鼠模型中的表达 IBD患者的肠道细胞。这项拟议的工作可能导致一种新的治疗IBD的策略，该策略基于一种新的 抑制CD40信号的途径。