Development of novel JAK3 inhibitors for the treatment of autoimmunity.

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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.