Chapter 12 Advances in the Discovery of Small Molecule JAK3 Inhibitors

Publisher Summary JAnus Kinase 3 (JAK3) is a member of the JAK family of non-receptor protein tyrosine kinases (PTKs) that include the closely related isoforms—namely, JAK1, JAK2 and tyrosine kinase 2 (TYK2). The realization that human defects in JAK3 signaling result in the clinical manifestation of a severe combined immunodeficiency (SCID) phenotype has suggested that selective JAK3 inhibitors may be useful as therapeutic agents in the areas of organ transplantation and autoimmune diseases. In addition, the promising clinical efficacy reported for the JAK3 inhibitor CP-690,550 in rheumatoid arthritis patients is noteworthy and suggests that obtaining efficacy comparable to, or perhaps better than, the current marketed biologic therapies in this disease may be possible with a small molecule. Although the highly selective inhibition of JAK3 for immunosuppression is particularly attractive from a safety perspective, it remains to be convincingly demonstrated in the clinic. While CP-690,550 does potently inhibit JAK3, it has been shown to inhibit to some extent other JAK family members—namely, JAK1 and JAK2, which may contribute to enhance efficacy in the clinic relative to purely selective JAK3 inhibition.