Janus kinase 3 inhibitor

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.

[5] This signaling process leads to phosphorylation and dimerization of the adaptor proteins STAT.

JAK3 is crucial in transmitting signals from cytokines that are responsible for either T-cell proliferation, differentiation, or development.

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.

The role of JAK3 is greatly restricted to the immune system, so this enzyme was thought to be a good target for selective immunosuppressant.

[1] Since JAK3 is not as ubiquitously expressed, selective targeting could improve tolerability, and decrease possible adverse effects and safety concerns.

[2] For example, dual inhibition of JAK1 and JAK3 might increase bacterial and viral infection because of a broader immunosuppressive effect.

[16] Sequence alignment has shown that the ATP binding pockets of the JAKs are almost identical and only a few features distinguish JAK3 from the rest.

One of these differences is the presence of cysteine residue (Cys909) in the front region of the ATP binding pocket, where the other JAKs have serine at that same position.

[20][3] To compare inhibitors, the parameter of choice is IC50; by measuring IC50 for different JAKs, determining selectivity is possible.