Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 6, Issue 1, 2007

Whereas G protein-coupled and nuclear receptors have been in the focus of the pharmaceutical industry since decades, protein kinases became interesting drug targets more recently. Several protein kinase inhibitors are well established for the treatment of tumors in the meantime, many more are in clinical development. Inside into the biology of protein kinases and progress in technologies to target these molecules, however, fostered the discovery and development of protein kinase inhibitors for the treatment of inflammation, too. They are particular promising since they are key factors in signal transduction with major impact for initiating, propagation and regulation of immunological responses. In addition, they are well “drugable” by small molecular weight inhibitors, opening the chance to discover oral bioavailable drugs. When considering kinases as targets in inflammation, however, there are several issues, too. These are mainly the selectivity of both the target and the inhibitor and the associated side effect profile of corresponding drugs. In contrast to application in oncology where efficacy is more or less the most important criteria, a high safety profile is key for the chronic treatment of usual non-life treating inflammatory and autoimmune diseases. Having said this, however, clearly better drugs with a favorable therapeutic index (effect / side effect ratio) are needed for these indications, too. Thus, to be considered as a really promising drug target the protein kinase of interest should be significantly involved in the inflammatory process - otherwise insufficient efficacy and potency would have to be expected - without being involved in other physiological processes of essential biological importance or a very selective expression pattern. The same is true with the specifity of the inhibitors itself. So a compound hitting just one other kinase a little may not be acceptable, depending on the function of these off target molecule. Consequently, a solid target identification and validation is needed before lead identification and optimization with the gaol of achieving high specifity is started. Despite all these challenges major progress has been made and the first promising kinase inhibitors are moving into the clinic for antiinflammatory therapy. There are many more on the horizon and it's pretty likely that protein kinase inhibitors will enrich the spectrum of therapy for chronic inflammatory and autoimmune diseases. Within this issue an overview is given on recent progress in the field of protein kinase inhibitors for the treatment of inflammation addressing the opportunities and chances on one hand and the issues and hurdles on the other hand. We are very pleased that we were able to convince real experts to contribute to this hot topic issue. Starting with some general points the recent findings are issued and should enable the reader to keep up with this fast developing field that is of substantial interest for basic and clinical orientated scientists on one hand and academia as well as pharmaceutical industry on the other hand.

Protein kinases are key factors in signal transduction, playing a pivotal role in the initiation, propagation and regulation of immunologic responses. In contrast to protein- protein interaction they are considered to be “drugable” by small molecular weight inhibitors. Thus kinases moved into in the focus as promising drug targets for the therapy of inflammatory and autoimmune diseases. Whereas some kinase inhibitors are in clinical development already, most others are in early stages of research or still require validation. Recently, major progress has been made in elucidating the complete human kinome, in understanding molecular mechanisms of protein kinase action in inflammation as well as in regard to technologies suitable for in vitro and in vivo target validation, inhibitor screening and its structural refinement. Starting with some general points, this review summarise some recent findings and developments and prepare the stage for the subsequent review articles published in this hot topic issue. It is the purpose to highlight both the opportunities and the issues associated with kinases as drug targets and to enable the reader to keep up with this fast developing field, that is of substantial interest for basic and applied scientists.

Protein kinases are major drug targets in pharmaceutical companies. A deep understanding of the features of the ATP binding niche is of utmost importance for the assessment of drugability and selectivity. This article focuses on recent developments in experimental and theoretical methods relating to structural aspects of drugability and selectivity. Predicting drugability is enabled by a detailed analysis of the structural characteristics of binding sites. Our in-house approach for the assessment of drugability and selectivity involves an interaction profile analysis (IPA) and is derived from available structural information of protein kinases. IPA as well as other methods introduced in this article can assist in explaining observed selectivity pattern. For a reliable prediction of selectivity of a protein it is necessary to enrich the currently available database by structural and affinity data.

Inflammation seems to be at the beginning of the majority of chronic diseases, and major efforts are dedicated to the development of anti-inflammatory drugs. Chronic inflammatory diseases, such as psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma, are diseases that affect a large segment of our population. Recent evidence suggests that even metabolic diseases, such as type 2 diabetes, and certain cardiovascular diseases, could also be considered to have an inflammatory origin. However, a chronic disorder that in its initial and even more advanced stages is often not life-threatening, presents a challenge for therapeutic intervention: companies have to develop drugs that are efficacious, relatively free of side effects, and can be used effectively for a long time. The identification of suitable targets, thus, depends on better understanding of the signaling pathways involved in the initiation and maintenance of inflammation. The availability of target validation technology, such as targeted mutagenesis in mice, gene silencing mediated by small interfering RNA and protein expression profiling in this context is of utmost importance. Here, we will focus on the latter two technologies.

Dysregulated protein kinase activity can cause severe human diseases. Consequently, there is a growing number of kinases that constitute candidate targets for pharmaceutical intervention. However, target validation is critical, since not all kinases are “druggable”, i.e. suitable as a selective drug target. In this review, we briefly introduce major strategies for generating mouse models to analyse and control the expression and function of distinct genes, to confirm specific inhibition of intended drug targets and to identify undesirable secondary effects in vivo. Focussing on tyrosine kinase 2 (Tyk2) and other Janus kinases (Jaks) as case studies we follow the path of investigations from in vitro towards in vivo experimentation. We give examples for the sometimes surprising consequences of the systemic absence of a distinct kinase; consequences that can not be easily deduced solely based on results from in vitro data. We discuss aspects of kinase functions that are distinct from their catalytic activity and give examples for cell-type specific functions. Potential pitfalls (e.g. embryonic lethality, species differences) of using mouse models as experimental systems for studying human diseases are discussed and strategies for improvements to deal with such complications are exemplified.

Tyrosine kinases play key roles in cell proliferation, differentiation, survival, cell migration, tissue development, and cell metabolisms. Mutation and /or truncation in tyrosine kinases result in their constitutive activation independent of ligand stimulation. The constitutively activated tyrosine kinase often triggers cancer development. Furthermore, it is well documented that overexpression of tyrosine kinases is involved in malignancy. In inflammatory lesion, tyrosine kinases are also activated via over-production of growth factors and/or cytokines from tissues. Several recent studies have demonstrated that targeting tyrosine kinases in inflammatory disease may lead to an useful therapy. In this review, we describe tyrosine kinases that are or may be involved in inflammatory disease such as stem cell factor (SCF) receptor (c-Kit), platelet derived growth factor (PDGF) receptors, macrophage colony stimulating factor (M-CSF) receptor (c-Fms), Trk receptors, vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor (FGF) receptors, epidermal growth factor (EGF) receptors, macrophage stimulating protein receptor (Ron), Janus kinases (Jak), and spleen tyrosine kinase (Syk)/zeta-chain associated protein kinase of 70 kDa (ZAP-70). In addition we describe potential tools and methods that can be applied for therapy, such as small molecule kinase inhibitors, antibodies, small peptides, or truncated receptors. Since inflammatory diseases are generally complex host reactions for a long term, and tyrosine kinases are important for maintenance of cell homeostasis, a successful tyrosine kinase targeting therapy will require many further studies.

A variety of different cell lineages of the hematopoietic system are activated during inflammatory processes. These cells not only contribute to the beneficial outcome of an immune response, but can also cause pathology such as autoimmunity as a consequence of extended or uncontrolled reactions. Therefore, an understanding of the basic mechanisms that lead to immune cell activation and the identification of key molecular players will also lead to strategies towards therapeutic manipulation of extended immune reactions. Members of the Tec kinase family (Bmx, Btk, Itk, Rlk and Tec) constitute an important class of non-receptor protein tyrosine kinases that are primarily expressed in the hematopoietic system. They are activated upon a variety of signals and are important participants of major signal transduction pathways in immunological processes. Hence, deficiencies in Tec family kinases cause several immunological defects, both in man and mice. Since Tec family kinases have been shown to function as modulators of immune cell activation, they may provide attractive drug targets for the manipulation of the immune response. In this review, we summarize recent data from studies about the activities of Tec family kinases in inflammatory cells and their role in in vivo models of infection, inflammation and autoimmune diseases.

The signal transduction pathways leading to activation of Jun-NH2-terminal kinase (JNK) and nuclear factor- κB (NF-κB) are activated by a plethora of extracellular signals. Small molecules have been developed that inhibit the JNK or IκB protein kinases. Additionally, several cell-penetrating peptides have been characterized that disrupt proteinprotein interaction domains within the NF-κB and JNK signalling pathways. Usually NF-κB and JNK are (re)viewed as separate signalling systems. However, emerging evidence suggests that both pathways are interconnected at various levels. In this review, the spatiotemporal control of JNK or NF-κ B activation is discussed in conjunction with cross talk mechanisms and various regulatory feedback loops. A detailed understanding of these mechanisms is important to optimize available strategies to interfere with NF-κB or JNK signalling.

Sequential activation of kinases (protein kinase cascades) is a general mechanism of signal transduction in many cellular processes. Several related intracellular signaling cascades have been found and characterized in the last 25 years known as mitogen-activated protein kinase (MAPK) signaling cascades. These cascades cooperate in transmitting extracellular signals to their intracellular targets and thus initiate cellular processes such as proliferation, differentiation, development, stress- and inflammatory response, and apoptosis. Each of these signaling cascades consists of protein kinases that sequentially in several steps activate each other by phosphorylation. MAPKs are ubiquitously expressed but regulate a variety of biological responses depending on the cell type. Modulating the function of MAPK pathways by small molecules therefore requires a profound understanding of how MAPKs are integrated in various signaling networks.