Novel Small Molecule Inhibitor of Rheumatoid Arthritis

描述(申请人提供)：LCK是一种由T细胞系淋巴细胞表达的非受体酪氨酸激酶。在T细胞中，Lck在抗原介导的激活信号的产生中起着至关重要的作用。由于T细胞激活是增强免疫反应的中心，抑制LCK可阻断T细胞激活并抑制免疫反应。因此，LCK是开发新型免疫抑制剂的理想靶点。基于这些生物学特性，我们采用了计算机辅助药物设计(CADD)和实验程序相结合的方法来寻找新的LCK抑制剂。针对LCK的SH2结构域的Py+3区域，已发现了一系列LCK抑制剂。这些化合物的一个子集已经被证明是Lck特异性的，而不是其他含有与Lck亲和力在低微摩尔范围内的Src家族激酶的SH2结构域。这些LCK选择性化合物在体外能抑制混合淋巴细胞反应，在小鼠窝淋巴结局部抑制同种异体反应，在体内抑制佐剂性关节炎大鼠实验模型。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，我们建议确定这些化合物的治疗效果的排名顺序。该第一阶段项目的目标是选择在第二阶段SBIR应用中提出的用于合成化学的先导化合物的先导优化。最终目标是FDA IND提交一种候选药物，用于类风湿性关节炎、多发性硬化症或其他慢性炎症性疾病的I期临床试验。 公共卫生相关性：类风湿性关节炎(RA)是一种慢性炎症性疾病，在美国和其他主要发达国家发病率很高，影响着200多万美国公民，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物和突破性的生物制剂，如靶向肿瘤坏死因子α。肿瘤坏死因子阻滞剂提高了部分患者的疗效，但这些药物的成本每年超过10,000-20,000美元。其他慢性炎症性疾病，如多发性硬化症，也可以通过这些昂贵的生物疗法进行治疗。对于在更大比例的患者中具有更高疗效和更具成本效益的药物，存在着大量未得到满足的医疗需求。该项目的具体目标是确定一种具有生物学效力、效力和安全性的先导化合物，适用于后续的铅优化和在与疾病相关的动物模型、安全药理学和毒理学中的深入评估。最终目标是开发一种治疗这些慢性炎症性疾病的有效候选药物，这种药物将比突破性的生物制剂具有更高的成本效益。

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.