ReviewKeynoteSpleen tyrosine kinases: biology, therapeutic targets and drugs
Introduction
In the past decade, important progress has been made in understanding the pathogenic mechanisms and defining the roles of relevant cells involved in allergic and autoimmune disorders. These breakthroughs facilitated the development of novel and effective drugs, such as the anti-IgE monoclonal antibody omalizumab (Xolair), which proved to be capable of inhibiting both acute airway constriction and, later, inflammatory eosinophilia [1]. In addition, treatment of rheumatoid arthritis (RA) has been revolutionized by the introduction of tumor necrosis factor-alpha (TNF-α) inhibitor biologics, which have also been demonstrated to suppress Crohn's disease, psoriasis and other chronic inflammatory conditions [2]. Although these protein therapies are highly effective, they are difficult and expensive to develop, manufacture and administer. Moreover, some of these targeted biological treatments are associated with relevant side-effects, such as the reactivation of tuberculosis and other latent infections. For these reasons, the current research goal is to explore new therapeutic approaches and generate safer, more efficacious and more cost-effective therapies with improved dosing schedules. Several targets are candidates, and they include cytokines, chemokines and factors that participate in the signal transduction pathways, such as proteins of complement, adhesion molecules and kinases [3]. In particular, a kinase with high potential for discovering novel inhibitors for the treatment of inflammatory and autoimmune disorders is spleen tyrosine kinase. This cytoplasmic protein kinase, discovered in 1991 [4], associates with different receptors on the surface of different cells of immune system (including B cells, mast cells, macrophages and neutrophils) and non-immune cells (such as osteoclasts and breast cancer cells). The engagement of these receptors with their ligands activates Syk, which, in turn, orchestrates different cellular processes, including cytokine production (in T cells and monocytes), bone resorption (in osteoclasts) and phagocytosis (in macrophages) [5]. In addition, because Syk is positioned upstream in the cell signaling pathway, therapies targeting Syk might be more advantageous than drugs that inhibit a single downstream event [6].
This makes Syk a therapeutic target for an array of inflammatory diseases and, for this reason, many pharmaceuticals companies (including Rigel, Pfizer, Bayer and ZaBeCor), as well as many academic institutions, have been involved in the development of small-molecule inhibitors of Syk.
Section snippets
Structure of Syk
The non-receptor spleen tyrosine kinase, along with zeta-chain-associated protein kinase 70 (ZAP-70), is a member of the Syk family of cytosolic protein kinases implicated in antigen and Fc receptor signaling. The two enzymes share a characteristic dual Src homology 2 (SH2) domain separated by a linker domain. SH2 domains typically bind to phosphorylated tyrosine residues within a motif contained in a target protein. This interaction initiates a cascade of events inducing several cellular
Syk kinases as a therapeutic target for disease
As described previously, Syk is a key mediator of immunoreceptor signaling in a host of inflammatory cells, including B cells, mast cells, macrophages and neutrophils. These immunoreceptors, including Fc receptors and BCR, are important for both allergic and antibody-mediated autoimmune diseases and, thus, interfering with Syk could conceivably represent a means of treating these disorders [6]. Several studies have highlighted Syk as a key player in the pathogenesis of a multitude of diseases (
Small molecules as Syk inhibitors
Several pathologies can be treated through the inhibition of Syk activity. The huge number of Syk-related patents and papers found in the literature is a further indication of its attractiveness as a therapeutic target. The great interest in this field is shown, not only by the increasing number of international applications in recent years but also by the noteworthy number of pharmaceutical companies and academic institutions that have been involved in the development of small-molecule Syk
Concluding remarks
Syk is a cytosolic non-receptor tyrosine kinase present in many cells, principally presiding over the inflammatory process. Inhibition of Syk activity is a valuable therapy in many pathologies, and a large number of small molecules have been synthesized and tested as Syk inhibitors. Therapeutic activity of some of them has already been demonstrated (e.g. the use of R788 in the treatment of RA) and they are currently in the advanced phases of clinical trials. Despite these encouraging results,
Mauro Riccaboni received his MS degree in Organic Chemistry in 2000 from Milan University. In 2002, he joined the pharmaceutical Medicinal Chemistry group of NiKem Research and, in 2006, was appointed Laboratory Head. He was involved as team leader in hit discovery, hit validation and lead optimization projects. Presently, his research work is focused on the development of drugs for the treatment of asthma and closely related respiratory diseases.
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Mauro Riccaboni received his MS degree in Organic Chemistry in 2000 from Milan University. In 2002, he joined the pharmaceutical Medicinal Chemistry group of NiKem Research and, in 2006, was appointed Laboratory Head. He was involved as team leader in hit discovery, hit validation and lead optimization projects. Presently, his research work is focused on the development of drugs for the treatment of asthma and closely related respiratory diseases.
Ivana Bianchi received her MS degree in Medicinal Chemistry in 2002 from State University of Milan with an experimental thesis carried out in the Medicinal Chemistry group of NiKem Research. Within the same company, she was involved as team leader in hit validation and lead optimization projects in the area of pulmonology. She was appointed senior scientist in 2008. Presently, her research work is focused on the synthesis of drugs for the treatment of chronic obstructive pulmonary disease (COPD).
Paola Petrillo received her Doctorate in Biological Science from Milan University, Italy, in 1983. She began her career at the Mario Negri Institute in 1979, where she spent 11 years working mainly in the opioid field. She then joined SmithKline Beecham, Italy and worked in the chronic pain and neuro-degenerative disease areas. In 2001, she was one of the co-founders of NiKem Research, a service provider in Drug Discovery. Now she is the Director of the Nikem Screening department. Paola Petrillo is the author of one patent and 30 articles in international journals.