Review
What makes a good anti-inflammatory drug target?

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This review focuses on the major, ‘successful’ target families in inflammation and attempts to identify some of the key features of what makes a good anti-inflammatory target. The review is based on a systematic analysis of approved anti-inflammatory drugs grouped according to their drug–target family. The cytokine family is a drug-dense area. They have yielded and continue to yield a rich stream of drugs. As in other therapeutic areas, G-protein-coupled receptors (GPCRs), also known as seven-transmembrane pass receptors, have provided significant drug targets. In addition, the superfamilies of cell adhesion molecules and co-stimulatory molecules, which have special relevance to immune processes, have begun to provide the first approved drugs and might yield many more. The recent, rapid increase in the number of defined targets in the immune system – leukocyte surface antigens, cytokines, GPCRs, adhesion molecules and co-stimulatory molecules – will ensure a rich stream of future anti-inflammatory drug targets.

Section snippets

What makes a good anti-inflammatory target? – The basic principles

There are some basic principles that guide the discovery and development of successful therapeutic targets. First, the target might be proximal to the initiation of the disease – not necessarily the very first initiating event but at least close to it. Second, the target could play a pivotal or driving role in the disease process – these targets are often at key regulatory points or rate-limiting steps in pathways (so that blocking such an event stops a whole series of downstream processes).

Cytokines as drugs and drug targets

Cytokines are a large family of proteins, comprising ∼93 members and ∼96 receptors that are key signaling mediators in immune systems. Figure 2 shows the ‘total known cytokine world’ and how it is divided into distinct subfamilies. The term cytokine is reasonably well-defined – soluble proteins produced by leukocytes or other cell types that act as chemical communicators between cells. In some cases the term can encompass growth factors, such as epidermal growth factor, transforming growth

Interleukins as drugs and drug targets

We can get a more detailed measure of the success and/or failure rates of cytokines by analyzing one of the subfamilies, the interleukins. Interleukins are cytokines that are largely, but not exclusively, produced by T cells, which are key cells involved in initiating and controlling immune responses. Hence, the T-cell-derived cytokines are likely to be pivotally important in inflammation. Interleukin (IL) numbers (e.g. IL-1) have been assigned in chronological order of discovery. It is

Adhesion molecules and CSMs

Adhesion molecules and CSMs play distinctive roles in inflammatory processes. Cell adhesion molecules (CAMs) are key players in mediating leukocyte migration from the vasculature blood stream to sites of inflammation and then leukocyte re-circulation to the lymphatic system and lymphoid organs. CAMs form specific pairings of receptors and ligands expressed on adjacent cells, leading to either transient or sustained intercellular adhesion. In addition, some CAMs link cells to the extracellular

GPCRs

GPCRs are integral membrane proteins characterized by having seven trans-membrane domains and also because they engage intracellular G proteins to initiate signaling cascades, upon ligand binding.

In many diseases they are a drug-dense family, particularly in the neuroscience and cardiovascular fields. Surprisingly, in the field of inflammation, GPCRs have yielded a relatively small number of validated drug targets. However, these targets have produced multiple, individual approved drugs that

Conclusions

This review has focused on using a combination of guiding principles (that define a good anti-inflammatory target) and an analysis of the approved anti-inflammatory drugs, making some rational statements about the future sources of new candidates.

To recap, the guiding principles that define good anti-inflammatory targets are: first, they are proximal to the initiation of the disease process; second, they are crucial to the driving force of the cascade; and third, they are specific to the

Acknowledgements

I would like to thank Mary Collins at Wyeth for Figure 2.

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