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