The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders

Abstract

Altered production of cytokines can result in pathologies ranging from autoimmune diseases to malignancies. The Janus kinase family is a small group of receptor-associated signaling molecules that is essential to the signal cascade originating from type I and type II cytokine receptors. Inhibition of tyrosine kinase enzymatic activity using small molecules has recently become a powerful tool for treatment of several malignancies. Twenty years after the discovery of these enzymes, two inhibitors for this class of kinases have been approved for clinical use and others are currently in the final stage of development. Here we review the principles of cytokines signaling, summarize our current knowledge of the approved inhibitors, and briefly introduce some of the inhibitors that are currently under development.

Figure 1. JAK inhibitors prevent JAK activation

The signaling cascade that originates upon binding of the cytokines to their specific receptors is blunted by the action of specific JAK inhibitors. JAKs are no longer capable to phosphorylate substrates like STATs and, therefore, cytokine-dependent gene regulation is prevented.