Janus kinase 3 inhibitor

Janus Kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus Kinase 3. They are uesed for the treatment of autoimmune diseases. The Janus Kinases is a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3 and TYK2. They signal via the JAK/STAT pathway which is important in regulating the immune system. Expression of JAK3 is largely restricted to lymphocytes (predominant expression is in the hematopoietic system), while the others are ubiquitously expressed, and therefore selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases.

Janus kinase 3 inhibitors work by inhibiting the action of the enzyme Janus Kinase 3 and therefore interferes with the JAK-STAT signaling pathway. JAK3 is required for signaling by cytokines through the common γ chain of the interleukin receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. However JAK1 is also required as the two kinases cooperate for signaling. Signaling leads to phosphorylation and dimerization of the adaptor proteins STAT. When activated they translocate into the nucleus where they modulate gene transcription. By selectively inhibiting JAK3, downward signaling can be blocked.

JAK3 is crucial in transmitting signals from cytokines that are responsible for either T-cell proliferation, differentiation, or development. It is also of high importance in the development of B-cells and NK-cells. Therefore, inhibition of JAK3, could prove to be a powerful immunosuppressant. Since JAK3 is restricted to the immune system, while the other JAKs such as JAK1 are much more broadly expressed, selective targeting of JAK3 could decrease possible adverse effects and improve tolerability.

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