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.

Introduction

Inflammatory responses are generally initiated by the recognition of signals that convey evidence of pathogen invasion or tissue injury. This, in turn, initiates the activation of intracellular signalling cascades and subsequently results in increased expression of proinflammatory cytokine genes. When these inflammatory responses occur in the absence of overt infection, or when the responses persist despite resolution of the initial insult, these processes can become pathological and result in chronic inflammation.

A wide spectrum of human diseases is associated with chronic inflammation and includes disorders such as psoriasis, rheumatoid arthritis (RA) and multiple sclerosis (MS). A number of well-established immune modulatory drugs have been used in the clinic for the treatment of these inflammatory and autoimmune diseases; however, these therapies have several limitations. Most current first-line therapies are either non-selective immunosuppressive or cytotoxic drugs, which are associated with limited clinical efficacy and significant side effects [1–3]. Furthermore, many patients either do not respond adequately or become unresponsive to such therapies. There is therefore a large unmet need in the treatment of these patients, prompting the search for new drug targets for the treatment of these inflammatory-mediated diseases.

As our understanding of the underlying inflammatory processes has advanced, increasingly sophisticated targeting of such pathways for therapeutic purposes has become a reality. An ideal therapeutic target would be a signalling molecule that plays an important role in the initiation of inflammatory responses but, in the context of other crucial cell mechanism-based events, is dispensable [4]. Much of the initial targeted therapeutic focus was on extracellular targets, with significant successes, including anti-tumour necrosis factor (TNF) and B cell-depleting therapies for RA and other inflammatory conditions. While undoubtedly significantly improving the treatment of these conditions, the current biological agents are not effective for all patients. Furthermore, even in those who respond, the majority have only a partial response with only a small minority achieving clinical remission. There therefore remains a significant unmet need in the treatment of chronic inflammatory conditions.

The drug development focus for inflammatory conditions has recently shifted more towards targeting intracellular signalling pathways. Protein phosphorylation, conducted by protein kinases, represents a major type of post-translational modification and is a fundamental mechanism of cell signalling [5–8]. Protein kinases are therefore an important class of intracellular enzymes that play a crucial role in most signal transduction cascades, from controlling cell growth and proliferation to the initiation and regulation of immunological responses [5,9–12]. Protein kinases, also referred to as phosphotransferases, phosphorylate their target proteins in cells by attaching phosphates covalently to the side chains of serine, threonine or tyrosine residues (Fig. 1). More recently, the potential importance of phosphorylation of histidine has also been recognized [13]. A total of 518 kinase genes encoding kinase proteins have been identified in the human genome, referred to collectively as the kinome [14].

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]).

Despite being first described almost 60 years ago by Burnett and Kennedy [15], the general significance of protein phosphorylation was only appreciated fully in the early 1980s (for a review, see [16]). Since then, the elucidation of protein kinase signalling cascades has been exponential [5], and includes the seminal studies by E. H. Fischer and E. G. Krebs, who were awarded the Nobel Prize in 1992 for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism [17–19]. Kinases have subsequently been shown to play an imperative role in the first steps of intracellular immune cell signalling. For example, kinases are associated physically with the intracellular component of receptors on the cell surface of T and B lymphocytes, and initiate intracellular signalling cascades within these cells once such receptors have engaged with their extracellular ligands [6]. Once it was established that protein kinases were the fundamental drivers of inflammatory cell signalling, they were investigated as therapeutic targets for a variety of diseases.

Protein kinase inhibitors

More than 400 diseases have been associated either directly or indirectly with protein kinases [20]. Thus protein kinases are now considered to be one of the most important groups of drug targets [10,21]. Kinases can be targeted by small molecular weight compounds which act to inhibit the phosphorylation of proteins, thus preventing their activation [4]. These small molecule inhibitors can interfere with kinase activity by either: (i) blocking adenosine triphosphate (ATP)-kinase binding, (ii) interfering with kinase–protein interactions or (iii) down-regulating kinase gene expression levels through the use of RNA interference strategies [20].

The success of kinase inhibitors in the treatment of cancer showcased their therapeutic potential (for a review, see [22]). This success, coupled with a greater understanding of inflammatory signalling cascades, led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases [23]. As such, a large body of research and review literature has developed around protein kinases and their inhibitors. In this review we describe the various classes of kinase targets, namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (SYK). We provide mechanistic insight into how these inhibitors interfere with kinase signalling pathways in the context of inflammatory and autoimmune diseases, as well as discussing the clinical successes and failures in the implementation of kinase-directed therapeutics, and their potential in the treatment of inflammatory-mediated diseases.

JAK family

Cytokines play essential roles in controlling all aspects of immune responses, including leucocyte differentiation and development, immunological tolerance and memory, and they are also responsible for driving many immune-mediated diseases [24]. JAKs serve to transduce signals from cytokine receptors, in particular types I and II cytokine receptors, which lack intrinsic kinase activity. Interferon (IFN) gene induction studies conducted in the early 1990s led to the discovery of the JAK–signal transducer and activator of transcription (STAT) pathway, the major signalling cascade downstream from cytokine and growth factor receptors [25,26]. This pathway consists of the JAK family of non-receptor tyrosine kinases and the STAT family of transcription factors [26]. A large number of cytokines (approximately 60) including IFN, colony-stimulating factors and interleukins (ILs) bind types I and II cytokine receptors, which are associated constitutively with JAKs [27]. These JAKS are essential for cell signalling and upon ligand binding the cytokine receptor dimerizes and triggers the activation of the JAK–STAT signal transduction cascade [28–30].

The mammalian JAK family comprises four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). They all share a similar structure characterized by the presence of seven JAK homology (JH) domains [26,31]. JAK1 and JAK3 are responsible for the signal transduction of cytokine receptors containing the IL-2 receptor common γ chain, thus mediating signalling by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines that are essential for the development and maturation of T lymphocytes (Table 1) [23,28,32]. Conversely, JAK2 is associated with haematopoietic growth factor receptors, as well as gp40-containing cytokine receptors [23]. JAK1, JAK2 and TYK2 are expressed ubiquitously in mammals, whereas JAK3 expression is limited mainly to haematopoietically derived cells [30,33,34]. As such, JAK3 is important for leucocyte activation and proliferation; namely, natural killer (NK), T and B cells [35].

Table 1.

Functions of Janus kinases (JAKs) and the phenotypes of knock-out mouse models.

Kinase	Cytokines requiring this JAK for signalling	Knock-out mouse phenotype
JAK1	Cytokines whose receptors contain the IL-2 receptor common γ chain: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21	Embryonic lethal
	Cytokines whose receptors contain the gp130 subunit (IL-6 family); IL-6, IL-11, IL-33 LIF, OSM, CT-1, CNTF, CLC
	IFNs
JAK2	Cytokines whose receptors contain the gp130 subunit (IL-6 family); IL-6, IL-11, IL-33 LIF, OSM, CT-1, CNTF, CLC	Embryonic lethal
	IL-3
	IFN-γ
	Hormone-like cytokines: EPO, GH, PRL, TPO
JAK3	Cytokines whose receptors contain the IL-2 receptor common γ chain: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21	SCID; however viable and fertile
TYK2	IL-12	SCID; however viable and fertile. Also susceptible to parasite infection
	LPS

CLC: cardiotrophin-like cytokine; CNTF: ciliary neurotrophic factor; CT-1: cardiotrophin-1; EPO: erythropoietin; GH: growth hormone; IFN: interferon; IL: interleukin; LIF: leukaemia inhibitory factor; LPS: bacterial lipopolysaccharide; OSM: oncostatin M; PRL: prolactin; SCID: severe combined immunodeficiency; TPO: thrombopoietin.

The importance of JAK signalling and its non-redundant, critical role in the initiation and regulation of inflammatory immune responses is best illustrated when JAKs are either mutated or deleted in vivo (Table 1) [36,37]. As JAKs proved to be critical for both innate and adaptive immunity, this family of protein kinases attracted significant attention as a new therapeutic target in inflammation and autoimmune disease [33,38].

JAK inhibitors

Walker et al. reported that JAK3 expression, as well as STAT-4,-5 and-6 expression, was increased in the synovium of patients with RA, compared with normal synovium [39]. This finding was confirmed in other studies, leading to selective inhibition of JAK kinases becoming a therapeutic strategy for the treatment of RA, as well as other inflammatory-mediated diseases.

It soon became clear that inhibiting JAKs would block multiple aspects of cytokine signalling (Fig. 2). One of the first selective JAK inhibitors to be tested in humans and enter clinical trials was tofacitinib (formerly known as CP-690, 550). Tofacitinib, developed by Pfizer (New York, NY, USA), is a potent JAK1 and JAK3 antagonist, which also inhibits JAK2 to a lesser extent [28]. Preclinical studies demonstrated tofacitinib's immunosuppressive effects in vivo in animal models of transplantation and arthritis [40–43]. Thereafter, tofacitinib entered clinical trials which confirmed its efficacy in RA [44,45]. Clinical studies have also suggested efficacy of tofacitinib in ulcerative colitis [46] and psoriasis [47]. In November 2012, tofacitinib was approved by the US Food and Drug Administration (FDA) for the treatment of patients with active RA who have failed other disease-modifying anti-rheumatic drugs (DMARDs), thereby becoming the first oral kinase inhibitor approved for the treatment of this disease. However, the European Medicines Agency (EMA) did not approve tofacitinib for RA due to concerns about the overall safety profile of tofacitinib, including unresolved concerns about the type and risk of serious infections [48].

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.

Despite its success in both preclinical studies and clinical trials, the exact mode of action of tofacitinib in the setting of autoimmune disease has yet to be ascertained fully [49,50]. Many of the cytokines that contribute to the pathophysiology of inflammatory-mediated autoimmune diseases signal through receptors associated with JAKs. It is well established that autoreactive CD4⁺ T cells [T helper (Th) cells], namely Th1 and Th17 cells, and their cytokines contribute to the pathophysiology of inflammation-mediated diseases such as RA and psoriasis [51–54]. A recent study by Ghoreschi et al. demonstrated that tofacitinib suppresses the generation of pathogenic Th1 and Th17 cells by targeting JAK1 and JAK3 kinases in T cells [28]. The authors used in-vitro T cell assays and murine models of collagen-induced arthritis (CIA) to confirm that tofacitinib acts to interfere with multiple cytokine signalling pathways in T cells, including IL-6 and IFN-γ, to attenuate the inflammatory response. Further studies will be required to validate which cytokines are blocked in patients undergoing tofacitinib treatment. The exact role and position of tofacitinib in the treatment pathway of inflammatory conditions remains unresolved, with studies under way to further evaluate its long-term safety in RA and its efficacy in other inflammatory immune-mediated diseases, including psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis and ulcerative colitis [55].

A variety of other JAK inhibitors (Fig. 2) have since entered clinical trials for the treatment of RA and other autoimmune disorders (Table 2). Ruxolitinib (INCB-018424), a JAK1 and JAK2 inhibitor already approved by the FDA for treating patients with myelofibrosis, has shown promising results in Phase II clinical trials for RA as well as a topical treatment for psoriasis [56,57]. Other JAK inhibitors demonstrating efficacy in Phase II RA clinical trials include GLPG-0634, a JAK1 inhibitor currently being developed by Galapagos (Mechelen, Belgium), and VX-509, a selective inhibitor of JAK3 developed by Vertex Pharmaceuticals (Cambridge, MA, USA) [58].

Table 2.

Janus kinase (JAK) inhibitors currently in development for inflammatory and autoimmune diseases.

Company	Agent	Target	Indication	Developmental status
Ambit Biosciences	AC-430	JAK2†	RA	Preclinical studies
Symansis	CEP-33779	JAK2†	RA	Preclinical studies
			SLE	Preclinical studies
Galapagos	GLPG-0634	JAK1†, JAK2, Tyk2	RA	Phase II
Cephalon	Lestaurtinib (CEP-701)	JAK2†	Psoriasis	Phase II
Incyte and Lilly	LY-3009104 (INCB-28050)	JAK1†, JAK2†	RA	Phase II
Incyte and Novartis	Ruxolitinib (INCB-018424)	JAK1†, JAK2†	RA	Phase II
			Psoriasis	Phase II
Rigel	R-348	JAK3†	RA	Phase I
Pfizer	Tofacitinib	JAK3†, JAK2†, JAK1	RA	FDA-approved (November 2012)
			Psoriasis	Phase III
			IBD	Preclinical studies
Vertex	VX-509	JAK3†	RA	Phase II

^†Denotes primary target of inhibitor. IBD: inflammatory bowel disease; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; FDA: Food and Drug Administration.

As cytokines are a central component in the pathogenesis of inflammatory and autoimmune disorders, these small molecule JAK inhibitors have the potential for treating a whole range of these diseases in addition to RA.

MAPK family

Another family of protein tyrosine kinases that play an important role in the regulation of fundamental biological processes are the mitogen-activated protein kinases (MAPKs). MAPKs are among the most ancient signal transduction pathways, and are conserved from yeast to mammals [59,60]. MAPKs act by phosphorylating specific serine and threonine residues belonging to target proteins, and are key regulators of a wide range of cellular processes, including gene expression, proliferation, differentiation and programmed cell death [59,61–63].

The MAPK superfamily can be broadly divided into conventional and atypical MAPKs. The conventional MAPKs consist of three major groups: (i) the p38 MAP kinases, (ii) the extracellular signal-regulated protein kinases (ERK), ERK1 and ERK2 and (iii) the c-Jun NH₂ terminal kinases (JNK) [64–66] (Fig. 3). Each of these MAPKs have their own specific roles in regulating cell function. For instance, ERK1 and ERK2 are expressed widely in all cell types and are important for cell proliferation and differentiation, whereas p38 exists as four isoforms (α, β, γ and δ), which play essential roles in the production of proinflammatory cytokines, including IL-1, IL-6 and TNF-α [67]. The three JNK isoforms (JNK1, JNK2 and JNK3) are all involved in extracellular matrix regulation by mediating metalloproteinase production [68]. The atypical MAPKs include ERK3/ERK4, ERK7 and Nemo-like kinase (NLK), and much less is known about the physiological functions of these MAPKs [66].

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.

The MAPK signalling cascade is activated in response to environmental stress cues, such as cytokines, Toll-like receptor (TLR) ligands and radiation (Fig. 3). In particular, proinflammatory cytokines activate p38 kinases, whereas growth factor receptor and cytokine receptor ligation initiate ERK signalling [67].

MAPK inhibitors

As MAPKs are involved in the production of proinflammatory cytokines, as well as the intracellular signalling cascades initiated when a cytokine binds to its corresponding receptor, they have attractive therapeutic potential and were the first kinases targeted with small molecule inhibitors. All three groups of the MAPK superfamily have been reported to be expressed in the synovial tissue of RA and osteoarthritis (OA) patients. However, MAPKs in their phosphorylated, active form have been detected only in RA synovium, suggesting that these MAPKs may be important in the pathogenesis of RA [69,70]. Preclinical studies have confirmed the therapeutic potential of p38 kinase inhibitors SB 203580 and SB 220025 in murine models of CIA, with both inhibitors preventing the progression of CIA [71,72]. Several MAPK inhibitors were subsequently developed and evaluated in RA (Table 3).

Table 3.

Mitogen-activated protein kinase (MAPK) inhibitors in clinical trials for inflammatory and autoimmune diseases.

Company	Agent	Target	Indication	Developmental status
Amgen	AMG-548	p38α	RA	Terminated – liver toxicity
Boehringer Ingelheim	Doramapimod (BIRB 796)	p38	RA	Terminated – liver and skin toxicities
Scios	SCIO-323	p38α	RA	Terminated – skin toxicity
Sigma-Aldrich	SB 220025	p38	RA	Preclinical studies
Vertex	VX-702	p38	RA	Phase II completed
Ferring Pharmaceuticals	Semapimod (CNI-1493)	JNK and p38	Crohn's disease	Phase II completed

RA: rheumatoid arthritis; JNK: c-Jun NH2 terminal kinases.

In addition to RA, MAPKs have been identified as important players in the pathogenesis of inflammatory bowel disease (IBD). IBD is associated with the up-regulation of proinflammatory cytokines such as TNF-α and IL-6, as well as activated p38 and MAPKs [73–75]. Preclinical studies by Hollenbach et al. reported improved clinical scores and reduced mRNA levels of proinflammatory cytokines with the p38 inhibitor SB203580 in a murine model of dextran sulphate sodium (DSS)-induced experimental colitis [76]. Early phase clinical trials with Semapimod (CNI-1493), a p38 kinase inhibitor, in Crohn's disease appeared promising, leading to further Phase III studies [77].

Despite their therapeutic appeal and promising early results in RA and IBD, most subsequent clinical trials have generally failed due either to poor efficacy or toxicity [6]. For example, the clinical trials of the p38 kinase inhibitors BIRB-796 and VX-745 in RA were both terminated as a result of adverse effects and associated toxicities, including hepatotoxicity and other liver function abnormalities [67,78]. The placebo-controlled trial of semapimod was ineffective for the treatment of moderate to severe Crohn's disease [79]. It has been suggested that the side effects associated with MAPK inhibitors have prevented the use of sufficiently high enough therapeutic doses in the clinic, resulting in the termination of such trials due to inadequate efficacy [2,79]. Furthermore, it appears that the inhibition of MAPKs may trigger compensatory mechanisms, as several clinical trials in RA resulted in a transient reduction in serum C-reactive protein (CRP) levels that were not sustained, suggesting that activation of alternative inflammatory pathways in RA patients diminished at the beginning of treatment, but then recovered 3 months later [80–82]. One approach to overcome this may be to target upstream signalling kinases, such as the MAPKKs or the MAPKKKs, in these pathways (Fig. 3). However, the utility of MAPK inhibitors as anti-inflammatory therapies in the clinical setting remains unresolved, particularly with the emergence of JAK and Syk inhibitors.

Syk

It is well established that classic immunoreceptors [i.e. B cell receptors (BCRs), T cell receptors (TCRs) and Fc receptors (FcRs)] initiate signal transduction via relatively similar mechanisms [83]. These immunoreceptors all contain immunoreceptor tyrosine-based activation motifs (ITAMs), located on the cytoplasmic domains of transmembrane proteins on the receptors [84,85]. ITAMs are short peptide sequences with two tyrosine residues, which are rapidly phosphorylated following receptor ligation which, in turn, induces the phosphorylation and recruitment of Syk or its related homologue, zeta-chain-associated protein kinase 70 (ZAP-70). This signalling cascade is now referred to widely as the central paradigm of immune cell signalling [83].

Syk is a 72 kDa cytosolic tyrosine kinase and belongs to the family of non-receptor type protein tyrosine kinases [86]. Syk was first described by Taniguchi et al. [87] and later identified as a critical signalling component required for the activation and development of B cells, as well as for mediating signalling through FcRs [88–90]. Syk is widely expressed in all haematopoietic cells and binds to the cytoplasmic domains of BCRs, as well as FcRs expressed on a variety of cells, including B cells, mast cells and neutrophils [91]. In addition, Syk mediates signalling of other cell surface receptors also found on non-haematopoietic cells, including β-integrins, receptors and TLR-4, as well as the collagen receptor glycoprotein V1 [92–96]. Syk is imperative for the initiation of signal transduction via these cell surface receptors and, as such, is especially important for orchestrating immune recognition receptors, as well as co-ordinating multiple downstream signalling pathways in leucocytes (Fig. 4). For example, Syk is associated with IgG (Fcγ) and IgE (FcεRI) receptors in granulocytes, and the activation of these receptors results in degranulation and the release of cytokines that contribute to allergic and proinflammatory responses [97].

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)].

Syk inhibitors

With Syk mediating the activation of sentinel cells (i.e. mast cells and macrophages), effector cells (i.e. neutrophils, eosinophils and basophils) and B cells, diseases such as RA, MS and SLE, where antibody-Fc receptor interactions are central to their pathogenesis, were identified as being potentially amenable to Syk suppression [98]. Several studies have suggested a role for Syk in the pathogenesis of RA, with Syk expression up-regulated in the synovium of patients with RA compared to control OA synovium, and Syk mediating proinflammatory cytokine production (Fig. 4) [99,100]. These data suggested that Syk inhibition could potentially interfere with the inflammatory processes that underlie RA, making Syk an attractive therapeutic target in RA.

The first selective Syk inhibitor developed for treating RA was fostamatinib (R788), an oral prodrug that is rapidly converted in vivo to a potent Syk inhibitor, known as R406. R788 showed promising results in preclinical studies, suppressing inflammation and joint damage in antibody-mediated mouse models of arthritis and in a T cell-mediated rat model of RA [99,101]. The initial Phases I and II clinical trials for RA in humans suggested that fostamatinib was well tolerated and efficacious, suppressing the severity of arthritis and resulting in a sustained decrease in IL-6 and matrix metalloproteinase-3 (MMP-3) levels [102,103]. However, a separate concurrent study in a different RA population group (patients with an inadequate response to biological agents) failed to reach its primary end-point [104]. Post-hoc analysis suggested that trial design could have adversely affected the observed outcomes [104,105]. However, the future of fostamatinib in RA remains unclear following the mixed therapeutic results in the Phase III studies.

As Syk-dependent functions in both haematopoietic and non-haematopoietic cells are central in the aetiology of inflammatory disorders, Syk inhibitors may therefore still prove to be efficacious in other immune diseases. Multiple Syk inhibitors are currently in clinical trials for the treatment of a variety of inflammatory-mediated diseases (Table 4). These trials include a Phase II clinical study of an inhaled Syk inhibitor, R343, for the treatment of allergic asthma, a chronic inflammatory disease of the airways [106]. Syk is essential for IgE receptor signal transduction in both mast cells and basophils, resulting in the release of proinflammatory mediators such as histamines, prostaglandins and cytokines [83]. R343 interrupts signal transduction via IgE receptors on mast cells, thus interfering with the major inflammatory pathways underlying the pathogenesis of asthma [107].

Table 4.

Spleen tyrosine kinase (SYK) inhibitors currently in development for inflammatory and autoimmune diseases.

Company	Agent	Indication	Developmental status
Bayer	BAY 61-3606	Allergic asthma	Phase IV (FDA-approved)
Sigma-Aldrich	ER-27319	Allergic diseases	Preclinical studies
Tocris Bioscience
Astrazeneca and Rigel	Fostamatinib (R788)	RA	Phase III – completed
Rigel	R112	Allergic rhinitis	Phase II – completed
Rigel	R343	Allergic asthma	Phase II
Rigel	R348	Keratoconjunctivitis sicca	Phase I – completed

RA: rheumatoid arthritis; FDA: Food and Drug Administration.

Concluding remarks

The ultimate goal in the treatment of autoimmune diseases is to suppress the pathological inflammatory component and restore immunological self-tolerance, while preserving the ability to mount an appropriate immune response against invading pathogens. Protein kinases are the key drivers of many inflammatory-mediated diseases and therefore represent an important and promising class of therapeutic targets in such disorders. The success of protein kinase-directed therapies in the treatment of cancer has spurred the search for small kinase inhibitors for the treatment of inflammatory and autoimmune diseases. To date, only a handful of kinase inhibitors have reached the stage of FDA approval, while others have had mixed results in clinical trials. In addition to the above kinase inhibitors currently undergoing clinical trials, inhibitors of other kinases, including JNK and ERK, have also been developed and await testing in humans. It therefore remains to be determined whether or not protein kinases will indeed turn out to be ‘the major drug targets of the 21st century’ [10], but this should become more clear as our understanding of the biology of these diseases and signalling pathways improves.

Disclosures

H. P. and R. N. have no conflicts of interest. I. M. has received honoraria from Pfizer, Astra Zeneca, Galapagos and Vertex. S. S has received honoraria, speaker's fees and conference sponsorship from Pfizer.