Editorial [Hot Topic: Protein Kinase Inhibitors for the Treatment of Inflammatory Disease (Guest Editor: Mark R. Player)]
Abstract: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.
Document Type: Research Article
Affiliations: Johnson and Johnson Pharmaceutical Research and Development, L.L.C. Spring House, PA USA.
Publication date: 2009-05-01