Small Molecule Therapeutic for Rheumatoid Arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种慢性疾病，主要表现为关节内层或滑膜的炎症。它会导致长期的关节损伤，导致慢性疼痛、功能丧失和残疾。在美国大约有210万人，占总人口的1%，患有类风湿性关节炎。它可以影响任何人，包括儿童，但70%的RA患者是女性。发病年龄通常在30至50岁之间。孕妇的类风湿性关节炎通常会缓解，尽管分娩后症状往往会加剧。类风湿性关节炎在分娩后一年的发病率比预期的要高。虽然女性患类风湿性关节炎的可能性是男性的两到三倍，但男性在患病时往往会受到更严重的影响。炎症和血管生成是病理紊乱的两个基本过程。组织损伤引起炎症，炎症引发血管生成，血管生成又启动组织修复和组织生长。持续的血管生成对于维持RA滑膜的慢性结构变化至关重要，通过传递营养物质和炎症细胞，并提供细胞因子和蛋白酶活性的重要来源。Met和Tie2是两种受体酪氨酸激酶，已被确定为抗血管生成的治疗靶点。使用药物发现引擎，Angion公司发现了小分子Ang797，这是一种与ATP竞争Met的ATP结合位点的活性激酶抑制剂。我们的研究结果表明，Ang797显著且选择性地抑制Met激活，并抑制其配体肝细胞生长因子/散射因子（HGF/SF）引发的下游信号事件。此外，Ang797还抑制另一种与血管生成相关的RTK Tie-2的活性。在体外，Ang797抑制内皮细胞和肿瘤细胞的生长，最相关的是，抑制HGF/ sf诱导的血管生成。在大鼠胶原诱导关节炎（CIA）模型中，Ang797可改善病程，减少组织损伤。我们的初步数据表明，Ang797及其类似物作为Met和Tie2激酶级联通路的特异性抑制剂，下调血管生成和新血管形成，改善疾病进程，促进CIA的功能恢复。在Angion，我们正在使用Met晶体结构、分子建模和药物化学方法来提高Ang797的效力。本申请旨在评价Ang797及其类似物在不同细胞系中抗ra血管生成活性的作用，确定其有效剂量，更好地了解Ang797及其类似物的体外作用机制。拟建的体内研究将为该Met和Tie2拮抗剂在动物模型中改善RA的能力提供重要的临床前疗效数据。该提案的主要重点是开发抑制SF/HGF/Met和Tie-2信号传导的小分子，以获得治疗优势。我们的先导化合物Ang797在治疗类风湿性关节炎方面具有高度创新性，具有显著的临床潜力。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic disease, characterized mainly by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. Approximately 2.1 million people in the United States, or 1% of the population, have RA. It can affect anyone, including children, but 70% of people with RA are women. Onset usually occurs between 30 and 50 years of age. RA often goes into remission in pregnant women, although symptoms tend to increase in intensity after delivery. RA develops more often than expected the year after giving birth. While women are two to three times more likely to get RA than men, men tend to be more severely affected when afflicted. Inflammation and angiogenesis are two of the fundamental processes that underlie pathologic disorders. Tissue injury induces inflammation, and inflammation triggers angiogenesis, which in turn, initiates tissue repair and tissue growth. Persistent angiogenesis is critical both to maintaining the chronic architectural changes in the RA synovium via delivery of nutrients and inflammatory cells, and to providing an important source of cytokines and protease activity. Met and Tie2 are two receptor tyrosine kinases that have been identified as therapeutic targets against angiogenesis. Using a drug discovery engine, Angion identified the small molecule Ang797, an active kinase inhibitor that competes with ATP for the ATP-binding site of Met. Our results indicate that Ang797 significantly and selectively inhibits Met activation and inhibits downstream signaling events initiated by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). Moreover, Ang797 also inhibits activity of a second RTK associated with angiogenesis, Tie-2. In vitro, Ang797 inhibits endothelial and tumor cell growth and, most relevant here, HGF/SF-induced angiogenesis. In the rat model of collagen induced arthritis (CIA), Ang797 ameliorates the disease course and reduces tissue damage. Our preliminary data show that Ang797 and its analogs act as specific inhibitors of Met and Tie2 kinase cascade pathways, down-regulate angiogenesis and neo-vascularization, ameliorate the course of the disease and promote functional recovery in CIA. At Angion, we are using the Met crystal structure, molecular modeling, and medicinal chemistry approach to increase the potency of Ang797. The goal of this application is to evaluate the anti-RA effects of Ang797 and its analogs on anti-angiogenesis activity in different cell lines, to determine the effective dose and to better understand the mechanism of action of Ang797 and its analogs in vitro. The proposed in vivo studies will provide important preclinical efficacy data regarding the ability of this Met and Tie2 antagonist to ameliorate RA in animal models. The primary focus of this proposal is the development of small molecules that inhibit SF/HGF/Met and Tie-2 signaling for therapeutic advantage. Our lead compound, Ang797 demonstrates highly innovative approach to the treatment of Rheumatoid Arthritis, with significant clinical potential.