**4.3 Janus-Associated Kinase (JAK) inhibitors**

The JAK family is composed of four tyrosine kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) (Fridman et al., 2011). Members of the JAK family are essential for signaling by many cytokines and growth factors following their binding to specific receptors on the cell surface. The interaction activates one or more JAKs, JAKs in turn activate the signal transducer and activator of transcription (STAT) proteins that transmit the growth and activation signals to the nucleus. JAK signaling is involved in a number of biologic processes, including the formation and development of blood cells and the regulation of immune function. Hyperactivation of JAKs has been associated with a number of disease states, including chronic myeloproliferative disorders and inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis (Fridman et al., 2001). As a result, JAK inhibitors are currently in clinical development for treatment of psoriasis both topically (INCB18424 from Incyte Corporation) and orally (Tofacitinib from Pfizer).

A 28-day phase Ib/IIa dose escalation trial of topical INCB18424 in patients with mild-tomoderate psoriasis demonstrated rapid onset of action, reduction in total lesion area, and improvement in lesion thickness, erythema, and scaling (Mesa 2010).
