Novel Small Molecule Inhibitor of Rheumatoid Arthritis

新型类风湿关节炎小分子抑制剂

• 批准号: 7667108
• 负责人: JUN HAYASHI HAYASHI
• 金额: $ 18.4万
• 依托单位: A AND G PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667108
• 关键词: Adjuvant Arthritis; Adverse effects; Affect; Affinity; Allogenic; Animal Model; Antigens; Area; Autoantibodies; Autoimmune Diseases; B-Cell Activation; Binding; Biological; Biological Assay; Biological Availability; Blood; Catalytic Domain; Cell Count; Cells; Chemical Agents; Chemicals; Chronic; Clinical Trials; Complex; Computer Assisted; Developed Countries; Developing Countries; Development; Disease; Drug Costs; Drug Design; Drug Kinetics; Evaluation; Experimental Models; Family; Generations; Glomerulonephritis; Goals; High Prevalence; Homologous Gene; Hyperplasia; ITAM; Immune response; Immunosuppressive Agents; In Vitro; Inflammatory; Lead; Lymphocyte; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Measures; Mediating; Medical; Mixed Lymphocyte Culture Test; Molecular Weight; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phosphotransferases; Phosphotyrosine; Play; Property; Proteins; Rattus; Receptor Protein-Tyrosine Kinases; Research; Rheumatoid Arthritis; Role; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Specificity; Splenomegaly; Synthesis Chemistry; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Therapeutic; Toxicology; Treatment Efficacy; Tumor Necrosis Factor-alpha; base; cost; cost effective; cytotoxic; design; drug candidate; functional group; human TNF protein; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; lymph nodes; novel; process optimization; programs; protein protein interaction; public health relevance; response; small molecule; src-Family Kinases

DESCRIPTION (provided by applicant): Lck is a Src family non-receptor tyrosine kinase expressed by T lineage lymphocytes. In T cells, Lck plays an essential role in the generation of antigen-mediated activation signals. Since T cell activation is central to mounting immune response, inhibition of Lck blocks T cell activation and suppresses the immune response. Accordingly, Lck serves as an ideal target for the development of novel immunosuppressant agents. Motivated by these biological properties, a combined computer-aided drug design (CADD) and experimental program was undertaken to identify novel Lck inhibitors. Targeting the pY+3 region of the SH2 domain of Lck a series of Lck inhibitors have been discovered. A subset of these compounds has been shown to be specific for Lck versus other SH2 domain containing Src family kinases with affinities for Lck in the low micromolar range. These Lck selective compounds inhibited mixed lymphocyte reaction in vitro, and popliteal lymph node local allogeneic responses in mice and adjuvant arthritis, a rat experimental model of rheumatoid arthritis in vivo. These compounds have therapeutic potential as immunosuppressants/modulators. In this application we propose to determine the rank order of these compounds for their therapeutic efficacy. The goal of this Phase I project is to select which lead compound for synthetic chemistry lead optimization to be proposed in a Phase II SBIR application. The ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in rheumatoid arthritis, MS or other chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory disease of high prevalence in the U.S. and the other major developed countries, affecting over 2 million U.S. citizens, resulting in over $3 billion in medical costs and other indirect expenses annually. The treatment of RA includes traditional pharmacological agents as well as breakthrough biologics, e.g. targeting TNF alpha. The TNF blockers have increased efficacy in a subset of patients but the costs of these drugs are in excess of $10,000 - 20,000 per year. Other chronic inflammatory diseases such as multiple sclerosis also are treated by these high cost biological therapeutics. There is a significant unmet medical need for drugs with increased efficacy in a larger proportion of patients and that are more cost effective. The specific aims of this project are designed to identify a lead compound with the biological efficacy, potency and safety suitable for subsequent lead optimization and in-depth evaluation in disease-relevant animal models, safety pharmacology and toxicology. The ultimate goal is development of an effective drug candidate for these chronic inflammatory diseases that will be substantially more cost effective than the breakthrough biologics.

描述（由申请人提供）：Lck是由T谱系淋巴细胞表达的Src家族非受体酪氨酸激酶。在T细胞中，Lck在抗原介导的活化信号的产生中起重要作用。由于T细胞活化是增加免疫应答的中心，因此Lck的抑制阻断T细胞活化并抑制免疫应答。因此，Lck是开发新型免疫抑制剂的理想靶点。受这些生物学特性的启发，结合计算机辅助药物设计（CADD）和实验程序进行了识别新的Lck抑制剂。针对Lck的SH 2结构域的pY+3区域，已经发现了一系列Lck抑制剂。这些化合物的一个子集已被证明是特定的Lck相对于其他SH 2结构域包含Src家族激酶与Lck的亲和力在低微摩尔范围。这些Lck选择性化合物在体外抑制混合淋巴细胞反应，并在小鼠和佐剂性关节炎，类风湿性关节炎的大鼠实验模型在体内的腘淋巴结局部同种异体反应。这些化合物具有作为免疫抑制剂/调节剂的治疗潜力。在本申请中，我们提出确定这些化合物的治疗功效的等级顺序。该第一阶段项目的目标是选择哪种先导化合物用于第二阶段SBIR应用中提出的合成化学先导优化。最终目标是FDA IND提交候选药物，用于类风湿性关节炎，MS或其他慢性炎症性疾病的I期临床试验。 公共卫生关系：风湿性关节炎（RA）是一种慢性炎症性疾病，在美国和其他主要发达国家中发病率很高，影响超过200万美国公民，每年导致超过30亿美元的医疗费用和其他间接费用。RA的治疗包括传统的药理学药物以及突破性的生物制剂，例如靶向TNF α。TNF阻滞剂在一部分患者中具有更高的疗效，但这些药物的成本每年超过10，000 - 20，000美元。其他慢性炎性疾病如多发性硬化症也可以通过这些高成本的生物治疗剂来治疗。对于在更大比例的患者中具有增加的功效并且更具成本效益的药物，存在显著未满足的医疗需求。本项目的具体目的是确定一种具有生物学有效性、效价和安全性的先导化合物，适用于随后的先导化合物优化和疾病相关动物模型、安全药理学和毒理学的深入评价。最终目标是开发一种有效的候选药物，用于治疗这些慢性炎症性疾病，这将比突破性生物制剂更具成本效益。