Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases

Abstract

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders.

Keywords: autoimmunity; novel biological therapies; protein kinases; signalling/signal transduction.

Figure 1

The catalytic cycle for protein phosphorylation by a protein kinase. Protein kinases mediate the transfer of the γ-phosphate (P) from adenosine triphosphate (ATP) to the hydroxyl group (OH) of a serine, threonine or tyrosine residue of the targeted protein. This phosphorylation acts as a ‘molecular switch’, which directly activates, or inactivates, the functions of proteins. However, protein phosphatases can oppose the kinase activities and reverse the effects of phosphorylation, by catalysing the removal of the γ-phosphate from the targeted protein (based on information taken from Grant [5]; Manning et al. [7]; Ubersax and Ferrell [8]).

Figure 2

Example of Janus kinase (JAK) inhibitors blocking cytokine signalling. Many cytokines exert their biological effects via the JAK–signal transducer and activator of transcription (STAT) pathway. As JAK inhibitors block JAK enzymes from initiating this signal transduction cascade, they also interfere with cytokine signalling. A variety of JAK inhibitors currently being evaluated in clinical trials interfere with more than one JAK. However, selective JAK inhibitors are also being developed.

Figure 3

The p38, Janus kinase (JAK) and extracellular signal-regulated protein kinase (ERK) mitogen-activated protein kinase (MAPK) signalling cascades. The mammalian MAPK superfamily consists of the p38, JNK and ERK families. Each MAPK signalling cascade begins with the upstream activation of MAPK kinase kinases (MAPKKKs), which phosphorylate MAPK kinases (MAPKKs) which, in turn, phosphorylate MAPKs. The activated MAPKs then translocate to the nucleus, where they phosphorylate transcription factors and modulate gene expression.

Figure 4

Spleen tyrosine kinase (Syk)-mediated cytokine signalling and Syk inhibitors. Syk inhibitors such as fostamatinib have been shown to inhibit tumour necrosis factor (TNF)-α signalling both in vitro and in vivo, therefore interfering with the production of proinflammatory cytokine interleukin (IL)-6 and the enzyme matrix metalloproteinase-3 (MMP-3) [active contributors to joint destruction in rheumatoid arthritis (RA)].