Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease

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Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.

Highlights

► Cytokines are critical contributors to autoimmune disease, cancer, and other diseases. ► Janus kinases (Jaks) selectively associate with type I and II cytokine receptors. ► Jaks have essential, nonredundant roles in mediating signals via these receptors. ► Ruxolitinib is approved for treatment of myelofibrosis, a disorder associated with Jak2 mutations. ► Tofacitinib has shown efficacy in trials in rheumatoid arthritis and other autoimmune diseases.

Introduction

Enabled by advances in molecular biology, it is now clear that an array of cytokines controls the growth and differentiation of hematopoietic cells and orchestrate all aspects of immune response [1]. From the differentiation of stem cells to the inciting events precipitated by activation of innate immune cells and the fine-tuning of helper T cell responses, cytokines play pivotal roles. However, cytokines are also fundamentally important for immune-mediated disease. A large segment of the population of industrialized countries suffers from asthma and allergy and a range of autoimmune diseases. In addition though, it is increasingly recognized that inflammation and dysregulation of cytokine production are directly involved in the pathophysiology of many other diseases including atherosclerosis and metabolic syndrome, degenerative neurologic disease, and cancer. For these reasons, therapeutic targeting of cytokines has immense potential.

The advent of monoclonal antibody technology and the ability to create therapeutically useful recombinant cytokine receptors has dramatically changed the therapeutic landscape of a wide variety of diseases. Thanks to ‘biologics’ debilitating diseases like rheumatoid arthritis (RA), which were previously associated with inexorable joint destruction, can be effectively treated. The question then arises: can the actions of cytokines be blocked by targeting intracellular signal transduction? In other words, might a pill be as efficacious as a parenteral biologic?

Section snippets

Janus kinases and signaling by type I/II cytokine receptors

The family of cytokines that bind type I and type II cytokine receptors includes interleukins, interferons, and colony-stimulating factor, as well as classic hormones such as erythropoietin, prolactin, and growth hormone [2]. Signaling via these receptors is dependent upon a small family of structurally distinct kinases with apparently circumscribed function (Figure 1). The Janus family of kinases (Jaks) comprises four members Tyk2, Jak1, Jak2, and Jak3 [3], which selectively associate with

Feasibility of kinases as therapeutic targets

At that time though, it was by no means a given that kinases were good therapeutic targets. Recall that this work preceded our present understanding of the human kinome. Of course, we now know that there are 518 kinases that can be divided into eight distinct families. Jaks belong to the tyrosine protein kinase family of which there are 90 other members. Because of the conserved kinase domain structure, it might be assumed that attaining the needed specificity to inhibit a certain kinase would

Targeting Janus kinases in autoimmune diseases and transplant rejection

The first selective jakinib to be tested in humans was tofacitinib (formerly designated CP-690,550). Tofacitinib potently inhibits Jak3 (IC 50, 2.2 nm) and Jak1 and to a lesser extent Jak2 (IC 50, 5.0 nm). It has little effect on Tyk2 (IC 50 260 nm) [20]. Remarkably, tofacitinib has potent activity against Jaks with little effect on other kinases [21•].

The utility of tofacitinib as an immunomodulatory drug was established in a variety of transplant models (murine and nonhuman primates) [22, 23] as

Targeting Jaks in myelofibrosis and polycythemia vera

A breakthrough in understanding the pathogenesis of the myeloproliferative diseases, polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) was the discovery of gain-of-function JAK2 mutations [47]. All of these mutations reside in the regulatory kinase-like domain, which has recently been found to have enzymatic activity [48]. In view of the success of imatinib in the treatment of CML, it was logical to consider that the development of a Jak2 inhibitor would be

Conclusions

Despite potential challenges, kinase inhibitors have emerged as an exciting new class of drugs. Given the key role of cytokines in many disorders ranging from malignancy to autoimmunity, Jak inhibitors or Jakinibs have the potential for wide utility in a range of diseases. They have demonstrated efficacy in PV/MF and an array of common autoimmune disorders. The extent to which Jakinibs will be used as steroid-sparing agents or even supplant the use of steroids in diseases like the vasculitides

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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