The introduction of biologic therapy in the last decade represented a major advance in the treatment of patients with moderate to severe psoriasis because it achieved a better response and was associated with lower toxicity than the systemic treatments previously used. However, a non-negligible percentage of patients (between 20% and 50%) respond insufficiently or not at all to biologictherapy.1 There is therefore an interest in identifying new drugs that may be effective in a larger number of patients. The identification of a number of psoriasis susceptibility genes, and with it a better understanding of the pathogenesis of the intracellular metabolic pathways (especially those related to cell signal transduction), has generated new perspectives on the treatment of psoriasis. In contrast to the experience of recent years, it is very likely that the new paradigm for psoriasis treatment will come not from new biologic agents with extracellular activity but from compounds with the ability to inhibit certain intracellular proteins involved in the immune response. The ideal target protein upon which these drugs are intended to work is one that possesses essential immune-cell functions that are also critical for the functioning of other cells. The inhibition of this target protein should modify the immune response triggered in psoriasis without affecting relevant organs. However, in many cases, these same proteins participate in other biological processes, and occasionally, these drugs may interact with related enzymes of the same type, making it difficult to predict their effects and potential adverse events.

The most rapid advances achieved with this new class of drugs have been made in the field of oncology, leading to current research on various drugs that block cytoplasmic proteins involved in the immune response to psoriasis, and other inflammatory diseases such as rheumatoid arthritis and Crohn disease. Their small molecular size allows them to be administered orally or topically, thereby potentially lowering the cost of treatment when compared with current biological drug treatment. Although still in the initial phases, the development of these drugs has been very rapid, and several are on the verge of approval for the treatment of inflammatory diseases other than psoriasis. It is possible that a number of these drugs will be completely defined for the treatment of psoriasis in the next decade.

Among the molecules currently under development for the treatment of psoriasis are those that act against certain protein kinases, which are intracellular enzymes found in all cells. These kinases activate or deactivate other proteins through phosphorylation, with the resulting transmission and amplification of information essential for the control of cell physiology.2 They exert this phosphorylation function through adenosine triphosphate molecules, and the majority of inhibitors act at this level. Protein kinases are essential for numerous membrane receptors, which do not have their own kinase activity and must interact with these proteins to transmit their signal from the exterior of the cell to the nucleus. The human genome encodes more than 500 different protein kinases, which are divided into 8 major didactic groups based on the sequence similarity of their catalytic domain (Table 1). The majority transfer phosphate groups to serine or threonine residues in a protein substrate. The most researched group in the field of psoriasis is the tyrosine kinase (TK) group.

Protein TKs (PTKs) are one of the primary groups of protein kinases and derive their name from their selective phosphorylation of tyrosine residues.3 There are an estimated 90 PTKs divided into 2 large families: receptor PTKs (cell membrane receptors with intrinsic kinase activity) and cytoplasmic or nonreceptor PTKs (Table 2). The latter, in turn, are divided into 9 subfamilies.4 Cytoplasmic PTKs are closely linked to essential cell functions such as the regulation of growth, division, differentiation, survival, and migration, as well as to the immune cell signaling system.2,5 They play a role in the nucleus in regulating the cell response to chemical signals, such as those from inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α]); pathogens, such as viruses; cell growth factors; and UV radiation. Cytoplasmic PTKs play an important role in the activation of lymphocytes, macrophages, neutrophils, and mast cells, and they also regulate diverse activities including hormonal activity, cell division, and gene expression.6

PTKs are clinically important because their activity is related to numerous diseases involving local inflammation, such as psoriasis and atherosclerosis, and other systemic inflammatory states, such as sepsis and septic shock. In addition, the expression of mutant or aberrant protein TKs may result in cancer due to uncontrolled cell division. Therefore, the blocking or inhibition of the activity of certain protein TKs represents an interesting therapeutic basis, for both neoplastic and inflammatory diseases. Numerous PTK inhibitor molecules have been developed that block the action of 1 or more protein kinases that, due to a particular mutation, are permanently activated in certain types of cancer. Initially, the development of protein kinase inhibitors was aimed at producing drugs with a high selectivity of action, although it has been subsequently shown that several of the compounds under development act on more than 1 kinase (multikinase inhibitors), and that each kinase can, in turn, act with various cytokines. In some cases, this relative lack of selectivity has been shown to be more of an advantage than a disadvantage because it opens up new therapeutic opportunities.

To date, 8 PTK inhibitors have been approved by the US Food and Drug Administration (FDA) for use in the treatment of organ tumors (renal, pancreatic, pulmonary, and gastric cell tumors) and lymphoproliferative disorders (chronic myeloid leukemia) (Table 2). New inhibitors are being developed for psoriasis, as well as for various inflammatory conditions such as rheumatoid arthritis, Crohn disease, and organ transplant rejection.7

Janus kinases (Jaks) are a subset of cytoplasmic PTKs that are crucial for the initiation of signaling pathways activated by cytokines; they are linked to the phosphorylation and activation of the signal transducer and activator of transcription (STAT) proteins. The activated STAT proteins control the expression of nuclear targets in the genes and induce the transcription of proinflammatory genes. Approximately 40 different cytokines and growth factors signal through STAT proteins.8 There are 4 types of Jaks: Jak1, Jak2, Jak3, and TK 2 (TYK2). These Jaks act in pairs in the intracytoplasmic portion of the cytokine receptor (Fig. 1). Each pair can be activated by different cytokines and, in turn, activate different STAT proteins (there are up to 6 types). Jak1 associates with interferon (IFN), interleukin (IL) 6 and IL-10 receptors, as well as with receptors containing the common γ chain. Jak2 associates primarily with hematopoietic receptors but it also associates with IL-12 and IL-23 receptors and acts as a dimer. Jak3 is the most specific type because it acts only with receptors that contain the common γ chain (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), in conjunction with Jak1.TYK2 associates only with the IFN receptor and with IL-12 and IL-23, in conjunction with Jak2. Therefore, the inhibition of a Jak will impede the action of more than 1 cytokine and, consequently, the transcription of genes responsible for inflammation and the control of innate and adaptive immunity. The cytokines that play a significant role in psoriasis, especially by acting on the keratinocyte, and those that use the Jak/STAT system are IFN-γ and IL-12, IL-19, IL-20, IL-22, IL-23, and IL-24. Other important cytokines are TNF and IL-17, but these do not use the Jak/STAT system.

Figure 1.

Schematic representation of the mechanism of action of the Janus kinase (Jak) inhibitors.

STAT indicates signal transducing proteins and activator of transcription; STAT-P,Phosphorylated STAT (active).

(0.2MB).

The spleen protein kinases (SYKs) are another family of cytoplasmic PTKs (Table 2) that play an important role in the signaling of immunoglobulin (Ig) E and IgG receptors in mast cells, basophils, and macrophages. As a result, these kinases also play an important role in the degranulation and release of cytokines and in proinflammatory and allergic responses.17 Fostamatinib is a prodrug that, once absorbed, becomes a potent and selective SYK protein inhibitor17; its efficacy has been demonstrated in rheumatoid arthritis.18,19 Phase II trials are currently underway for the oral treatment of psoriasis.

The epidermal growth factor receptor (EGFR) is a protein with intrinsic TK activity (Table 2), which is elevated in psoriasis plaques. There are published cases of patients with cancer treated with EGFR inhibitors (erlotinib) whose psoriasis improved.20–22 A phase II trial using erlotinib for the treatment of patients with psoriasis was therefore started, but it was suspended before patient selection due to unknown reasons.

Masitinib (AB1010) is a TK inhibitor (primarily of c-kit) that has anti-mast cell properties and is being tested in several neoplastic and inflammatory diseases, such as asthma, mastocytosis, gastrointestinal stromal tumors, and rheumatoid arthritis. There is a phase II trial underway for the oral treatment of psoriasis.

CT327 is a TrkA kinase inhibitor (a receptor-type PTK) of the TRK family (Table 2) and acts as a high-affinity nerve growth factor receptor, which has also been implicated in the pathogenesis of psoriasis. Trials are being conducted using the topical administration of this drug for the treatment of psoriasis and atopic dermatitis; 1 phase II trial has been completed and another trial, using different concentrations of the drug, is currently underway.

The protein kinase C (PKC) family is classified within the group of proteins bound to protein G (AGC) (Table 1) and has an important role in the adaptive immune system and therefore in the control of inflammatory diseases. To date, 12 isozymes are known, which possess different amino acid sequences and regulatory mechanisms. They are divided into 3 subfamilies according to their structure and type of action (classical, novel, or atypical). They are expressed in various types of cells that regulate immunological processes such as the development, differentiation, and activation of lymphocytes and the activation of macrophages and dendritic cells.23

Another group of protein kinases involved in various regulatory cell pathways and inflammatory cytokine production are the mitogen-activated protein (MAP) kinases, which include the p38 protein. These kinases form part of the cyclin-dependent kinase group (CMGC, named after the initials of some of its members) (Table 1). The p38 protein has awakened great interest as a potential molecular target for the treatment of inflammatory diseases, such as psoriasis, because it is an important enzyme in cell signaling for the synthesis of anti-inflammatory cytokines such as IL-10 in macrophages and proinflammatory cytokines such as IL-1β and TNF-α.26

However, phase II clinical trials studying the use of p38 protein inhibitors in rheumatoid arthritis have not produced the expected benefits, and to date more than 20 different orally administered p38 inhibitors have been investigated in phase I/II clinical trials for a variety of clinical indications. None of these trials have progressed to phase III,27 mainly due to the adverse effect profile.BMS-582949 is the only p38 MAP inhibitor that has undergone phase II trials for the oral treatment of psoriasis.

Kinase inhibitors are a new paradigm in the treatment of psoriasis. Their future role within the therapeutic arsenal is still uncertain, and we still do not have data from phase III trials. Kinase inhibitors consist of small molecules that inhibit intracellular signaling pathways. They primarily act by blocking more than 1 kinase and inhibiting the action of various cytokines, meaning that their mechanism of action is not particularly selective. Kinase inhibitors represent an innovation, considering the many years since the introduction of orally and topically administered drugs for the treatment of psoriasis. These administration routes may prove useful in lowering the price of kinase inhibitors when compared with biological drugs and facilitate the approval of these inhibitors for the treatment of psoriasis.

The most advanced compound in terms of research is tofacitinib, which has shown promising results in phase II trials. Its safety profile appears to be acceptable but this has yet to be confirmed in phase III trials. Nevertheless, the use of tofacitinib will require biochemical monitoring as it may reactivate tuberculosis.

The authors declare that they have no conflicts of interest.