Current Topics in Medicinal Chemistry - Volume 9, Issue 7, 2009

A variety of chronic inflammatory and immune-mediated diseases cause undue patient pain and suffering, and represent significant areas of unmet medical need. Rheumatoid arthritis is a chronic systemic inflammatory disorder which affects almost one percent of the world's population, and its long-term treatment is underserved by existing disease-modifying antirheumatic drugs. Chronic obstructive pulmonary disease, characterized by the dyad of chronic bronchitis and emphysema, is treated symptomatically with bronchodilators as well as corticosteroids. Asthma is a chronic, prevalent, respiratory condition manifesting bronchospasm with an element of underlying inflammation. Like COPD, there are a paucity of disease-modifying treatments for asthma. Multiple sclerosis is an autoimmune disease that attacks the nervous system, resulting in demyelination, and is frequently progressive and debilitating. For these conditions, symptomatic relief and disease modification with biologic agents are the current standard of care, but inhibition of a number of different kinases offers the opportunity to intervene in inflammatory and immune-mediated disease in a new way. Almost all aspects of cellular function are controlled, at least in part, by protein phosphorylation. Approximately 518 tyrosine and serine/threonine kinases are known to be encoded by the human genome, and about a third of proteins contain covalently bound phosphate. As key components of signaling pathways regulating immunoreceptors, kinases serve to control downstream targets with respect to proliferation, differentiation and survival of immune cells, both within the innate and adaptive immune systems. Kinase drug discovery has witnessed remarkable advances over the last decade. Inhibitors of thirty kinase targets have progressed as new molecular entities into Phase 1 clinical trials, while several kinase inhibitors have gained approval as drugs. Although the majority of kinase inhibitors that have reached the clinic are targeted toward the treatment of cancer, inhibitors for the dysregulated kinases implicated in many immune-mediated and inflammatory disorders are advancing as well. Small molecule kinase inhibitors may have inherent advantages over the biologic agents currently used to treat rheumatoid arthritis and multiple sclerosis, with respect to cost and ease of administration. Fears of off-target activity of ATP-competitive kinase inhibitors plagued early programs, and while some chemical scaffolds have been found to be relatively promiscuous, several factors have enabled selective compounds to be identified. Structural knowledge, largely in the form of x-ray cocrystal structures which have been obtained with many kinases, as well as the commercial availability of enzymatic or binding assays for over four hundred separate kinases, have enhanced the ability of drug discovery researchers to develop very selective drug candidates.

FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is overexpressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as well as autoimmune and inflammatory disease, such as rheumatoid arthritis (RA). Numerous FMS inhibitors with structurally distinct chemotypes have been developed and exhibit potent in vitro activity, but only a limited number of compounds have progressed clinically due to poor selectivity. To date, only a handful of FMS inhibitors have been tested in models of metastatic bone disease and RA. This review will summarize the biology of FMS and its function in bone physiology, inflammation, immunity, and cancer. In addition, efforts directed towards identifying FMS-selective small molecule inhibitors as well as the advancement of non-selective inhibitors in the clinic will be highlighted. Furthermore, emerging monoclonal antibody-based therapeutic strategies specifically targeting M-CSF will be described.

Cot/Tpl-2/MAP3K8 is a serine/threonine protein kinase that is essential for lipopolysaccharide (LPS)-induced activation of the MEK/ERK pathway in macrophages as demonstrated in Cot/Tpl-2-deficient mice. Cot/Tpl-2 kinase activation plays an integral role in the production of pro-inflammatory cytokines such as TNF and IL-1β in this immune cell type. Elevated levels of these cytokines have been clinically implicated as mediators of a number of autoimmune diseases, in particular, the pain and joint destruction of rheumatoid arthritis. By inference, pharmaceutical agents that inhibit Cot/Tpl-2 kinase have the potential to be novel and effective therapies for the treatment of these diseases. This review will describe the physiological regulation and importance of Cot/Tpl-2 in inflammation as well as the landscape of small molecules that have been reported as Cot/Tpl-2 inhibitors.

The IκB kinases (IKKs) are essential components of the signaling pathway by which the NF-κB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFα). NF-κB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders including rheumatoid arthritis (RA), chronic obstructive pulmonary disorder (COPD), and asthma. Inhibition of the kinase activity of the IKKs is therefore a promising mechanism for intervention in these diseases. Here, we will review the literature describing small molecule inhibitors of IKKβ (IKK2), the most widely studied of the IKKs.

Members of the protein kinase C (PKC) family of serine/threonine kinases have been targeted for drug discovery for over 20 years, initially focusing on inhibitors of the classic PKCs, which include the α, β, and γ isoforms. Recently, inhibition of the activity of the novel PKC isoforms, namely θ, δ, η, and η, has become a focus of research. PKCθ, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. While T cells play critical roles in initiating and controlling the immune response, inappropriate or extended stimulation of T cells is responsible for many chronic inflammatory diseases. Mice with an engineered deficiency in PKCθ have reduced incidence and severity of several inflammatory disorders including asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and allograft rejection. This review summarizes the efforts directed towards the design of small molecule PKCθ inhibitors as potential therapeutic agents.

Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) α and interleukin (IL) 1β. The clinical benefit of anticytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of proinflammatory cytokines such as IL-1β and TNF-α [6] suggest that p38 MAP kinase is a promising target for antiinflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.