Development of novel JAK3 inhibitors for the treatment of autoimmunity.

慢性炎症和自身免疫性疾病，如类风湿关节炎、牛皮癣和炎症性肠病，是英国的一个重要问题。例如，英国估计有40万人患有类风湿性关节炎，180万人患有牛皮癣，26万人患有炎症性肠病。这些疾病往往是长期的，可能会严重削弱。目前的治疗方法侧重于抑制身体的免疫系统，目的是阻止疾病的发展。然而，目前用于治疗这些疾病的药物存在两个主要问题。长期免疫抑制治疗有严重副作用的风险，包括但不限于严重和可能危及生命的感染以及癌症发病率的增加。此外，并非所有患者都对现有的一线药物有反应，而最近开发的“生物”药物，如抗肿瘤坏死因子治疗，价格昂贵，必须通过注射给药。因此，一种有效的口服药物将是治疗这些疾病的重大进展。自身免疫性疾病的一个共同特征是，免疫系统失去了只对病原体作出反应的能力，开始识别身体的外来成分。这会引发免疫激活，导致慢性炎症和不可逆的组织损伤。这个过程依赖于一种叫做细胞因子的蛋白质的产生，这种蛋白质可以激活免疫细胞并引发炎症。为了激活免疫细胞，细胞因子必须开启细胞内的特定信号蛋白。其中一个重要的例子是一组4个相关的蛋白质，称为“Janus激酶”或jak。阻断jak的活性会使免疫细胞失活，从而防止炎症。支持这一观点的证据来自一种名为托法替尼（Tofacitinib）的药物，该药物在自身免疫性疾病的临床试验中被证明是有效的。然而，托法替尼的广泛使用可能由于在少数接受该药的患者中可以看到的不良副作用而被阻止。尽管托法替尼在美国已被批准用于治疗某些类型的类风湿关节炎，但对这些副作用的担忧阻碍了它在英国的批准。尽管存在缺陷，但托法替尼已经证明抑制JAKs是治疗一些自身免疫性疾病的一种很有前途的新方法。现在的一个关键问题是，是否可以发现新的JAK抑制剂，提高治疗自身免疫的能力，但副作用更少。Tofacitinib抑制JAK家族的多个成员，这种广泛的抑制可能会引起一些脱靶效应。一种更具选择性的JAK抑制剂可能能够以更小的毒性提供所需的益处。在这方面，JAK3是一个有吸引力的靶标，因为与JAK1和JAK2不同，JAK3只存在于免疫系统的细胞中。此外，已知使JAK3失活的突变会抑制免疫系统。我们已经确定了一种新的抑制剂，它通过靶向JAK3独有的位点来阻断JAK3的活性，而JAK3家族的其他成员中没有发现这种位点。该项目将围绕这种分子进行“打铅”化学反应，目的是在关节炎小鼠模型中口服具有活性的铅分子。我们还将使用一种被称为化学遗传学的新技术来证明该药物在小鼠中的作用是由于其抑制JAK3的能力，而不是化合物的脱靶效应。这项工作构成了药物开发的早期阶段，该项目的目标是提供一种新的潜在药物，适合进入后期先导优化，临床前测试，然后进入临床试验。

Chronic inflammatory and autoimmune disorders, such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, represent a significant problem in the UK. For example, an estimated 0.4 million people in the UK suffer from rheumatoid arthritis while psoriasis affects 1.8 million and inflammatory bowel disease affects 260000. These diseases are often long term and can be severely debilitating. Current treatments focus on suppressing the body's immune system with the aim of arresting disease progression. There are however two main issues with the drugs currently available to treat these conditions. Long-term immunosuppressive therapy caries a risk of serious side effects that include, but are not limited to, serious and potentially life-threating infections as well as an increased incidence of cancer. In addition not all patients respond to the available 1st line drugs while the recently developed "biological" agents, such as anti-TNF therapy are expensive and must be administered by injection. An effective orally available drug would therefore represent a significant advance for the treatment of these diseases.A common feature of autoimmune conditions is that the immune system loses that ability to react only to pathogens and starts to recognize components of the body as being foreign. This triggers immune activation leading to chronic inflammation and irreversible tissue damage. This process depends on the production of proteins termed cytokines that activate immune cells and drive inflammation. To activate an immune cell, cytokines must turn on specific signaling proteins inside the cell. One important example of this is a group of 4 related proteins referred to as "Janus kinases" or JAKs. Blocking the activity of JAKs would deactivate the immune cell and therefore prevent inflammation. Evidence to support this comes from a drug, Tofacitinib, which has proven effective in clinical trials for autoimmune diseases. Widespread use of Tofacitinib may however be prevented by the adverse side effects that can be seen in a minority of patients receiving the drug. Although Tofacitinib has been approved for use in the US for treating some forms of rheumatoid arthritis, concerns over these side effects have prevented its approval in the UK. Despite its drawbacks, Tofacitinib has demonstrated that inhibition of JAKs is a promising new way for treating some autoimmune diseases. A key question now is whether new JAK inhibitors could be found that have an improved ability to treat autoimmunity but have fewer side effects. Tofacitinib inhibits multiple members of the JAK family, and this broad inhibition may give rise to some of the off target effects. A more selective JAK inhibitor may be able to deliver the required benefits with less toxicity. JAK3 is an attractive target in this respect as, unlike JAK1 and JAK2 that are found in many cell types in the body, JAK3 is only found in cells in the immune system. Furthermore mutations that inactivate JAK3 are known to suppress the immune system. We have identified a new inhibitor that blocks JAK3 activity by targeting a site that is unique to JAK3 and not found in the other members of the family. The project will carry out "hit to lead" chemistry around this molecule with the aim of delivering lead molecules orally active in a mouse model of arthritis. We will also use a new technique, referred to as chemical genetics, to show that the action of the drug in mice is due to its ability to inhibit JAK3 and not an off target effect of the compound.This work constitutes the early stages of drug development and the aim of the project will be to deliver a new potential drug that is suitable to advance in to late lead optimization, pre-clinical testing and then into clinical trials.