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GlaxoSmithKline's IkappaB kinase 2 (IKK-2) inhibitor, TCPA-1 as a potential next generation disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis

Posted on: 15 Sep 04

Summary

The TNF blockers Enbrel (etanercept) and Remicade (infliximab), have contributed to a revolution in the treatment of rheumatoid arthritis. The drug development community is now expending considerable resources on developing next generation disease modifying antirheumatic drugs (DMARDs) with improved efficacy and safety as well as oral activity. GlaxoSmithKline's IkappaB kinase 2 (IKK-2) inhibitor, TCPA-1 has recently been developed and has shown considerable promise in early stage development.

The TNF blockers Enbrel (etanercept) and Remicade (infliximab), have contributed to a revolution in the treatment of rheumatoid arthritis. The drug development community is now expending considerable resources on developing next generation disease modifying antirheumatic drugs (DMARDs) with improved efficacy and safety as well as oral activity. GlaxoSmithKline's IkappaB kinase 2 (IKK-2) inhibitor, TCPA-1 has recently been developed and has shown considerable promise in early stage development.

(Editorial note: In depth reports on rheumatoid arthritis can be found at LeadDiscovery's report center or click here for suggested reading on the treatment of rheumatoid arthritis)

DailyUpdates 15th September, 2004: An estimated 5 million individuals suffer from rheumatoid arthritis in the Western world. Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs; however, their clinical benefit for rheumatoid arthritis often diminishes with time. This, the severe rebounds observed following the withdrawal of corticosteroids, and long-term systemic side effects associated with corticosteroids limits their use in the treatment of rheumatoid arthritis.

Due to the problems associated with steroids, the treatment of rheumatoid arthritis has changed remarkably over recent years. Significant efforts have resulted in the development of the COX2 inhibitors celebrex and vioxx, although these agents treat the symptoms of rheumatoid arthritis and have little impact on disease progression. One of the most exciting developments in the management of rheumatoid arthritis has been the introduction of the anti-TNF biologics. These disease modifying antirheumatic drugs (DMARDs) represent a real step forward in the development of inflammatory/autoimmune disorders in general.

According to some analysts, new therapeutic approaches centered on biologic therapies will drive the market for autoimmune disorders to grow at a rate of over 15%, to a value of over $21 billion by 2006. The first biologic for the treatment of rheumatoid arthritis, etanercept (Enbrel) was approved in 1998. Since the late 1990's growth in the biologics market has been remarkable and sales of this therapeutic class for the treatment of autoimmune disease reached approximately $6.8 billion in 2003 (for an evaluation of biologics in autoimmune disease click here).

The TNF-alpha decoy receptor, Enbrel and Remicade (infliximab), a TNF-alpha monoclonal antibody dominate the US and European rheumatoid arthritis markets, accounting for more than 80% of value sales. New biologics set to enter the market include CDP 870, Rituxan and CTLA4-Ig (for an analysis of emerging DMARDs click here). Sales are predicted to follow the exponential growth curves of Enbrel and Remicade with long 'take-up' phases. Despite the success of biologics an opportunity remains for an effective oral DMARD and the identification of molecular targets and corresponding non-petide therapeutics for future treatments of rheumatoid arthritis continues in earnest (click here for LeadDiscovery's evaluation of emerging targets)

One candidate for the future treatment of rheumatoid arthritis, TCPA-1 an inhibitor of IkappaB kinase 2 (IKK-2) has recently been developed by researchers at GlaxoSmithKline.

Rheumatoid arthritis is driven by increased expression of a number of proinflammatory molecules including TNF-alpha, IL-1, IL-6, IL-8, IFN-gamma, intercellular adhesion molecule-1, vascular cell, adhesion molecule-1, cyclooxygenase (COX)-2, inducible nitric oxide synthase, matrix metalloproteinase (MMP)-1, and MMP-9. Expression of these mediators is regulated by the Rel/NF-kappa B family of transcription factors. Thus, members of this signaling pathway may represent better targets for the development of novel rheumatoid arthritis therapeutics than existing therapeutics that modulate single inflammatory mediators.

NF-kappa B is retained in the cytoplasm in an inactive form through its association with I-kappa B proteins. A variety of stimuli, including TNF-alpha and IL-1, are capable of inducing NF-kappa B activation and its subsequent localization to the nucleus. Much evidence indicates a pivotal role for NF-kappa B in the etiology of rheumatoid arthritis. Nuclear localization of NF-kappa B is increased in synovial tissue from patients as well as in animals with experimental arthritis and this is inhibited by classical anti-rheumatic agents.

Inflammatory mediators initiate a signaling cascade leading to the phosphorylation of two N-terminal serine residues in I-kappa B, which facilitates the ubiquitination and subsequent degradation of I-kappa B. The enzymes responsible for the ubiquitination of phosphorylated I-kappa B are constitutively active and phosphorylation of I-kappa B by the I-kappa B kinase (IKK) complex represents a key regulatory step. IKK-2 mediates TNF-alpha and IL-1-induced NF-kappa B activation and IL-6 production suggesting that IKK-2 inhibitors may be therapeutically active. Indeed articular gene transfer of wild-type IKK-2 produces paw swelling and synovial inflammation, while transfer of a dominant negative IKK-2 gene decreased the severity of disease.

In an upcoming edition of the Journal of Pharmacology & Experimental Therapeutics, Podolin et al describe the identification of TPCA-1as a the non-peptidic small molecule inhibitor of IKK-2. TPCA-1 inhibited human IKK-2 activity with nanomolar potency. Inhibiting this enzyme blocked the production of inflammatory mediators in LPS-stimulated human monocytes demonstrating that TPCA-1 effectively prevents the NF-kappa B signaling pathway in intact cells. NF-kappa B activation was shown to correlate closely with the appearance of disease in the CIA model of rheumatoid arthritis and the intra peritoneal administration of TPCA-1 limited the development of disease. Perhaps more importantly, as well as being active prophylactically, TPCA-1 was also able to reverse established inflammation albeit at higher doses. The efficacy of TPCA-1 was similar to that of etanercept.

This important study demonstrates the TPCA-1 may be a candidate not only for the prevention but also for the treatment of rheumatoid arthritis. Worldwide, over half a million patients have been treated with TNF-alpha blockers and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis; likewise an association between non-Hodgkin's lymphoma and treatment with TNF-alpha blockers has been reported. Large phase II and III trials have also shown a detrimental effect of TNF-alpha blockers in advanced heart failure. TPCA-1 which has a different mechanism of action to existing TNF-blockers may have an improved safety profile. This, the possibility of oral activity and improved clinical efficacy await further investigation.

Source: Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent and Selective Small Molecule Inhibitor of I{kappa}B Kinase 2, TPCA-1, Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation. J Pharmacol Exp Ther. 2004 Aug 17 [Epub ahead of print]

This article is highlighted in the September 15th edition of DailyUpdates-Immunology & Inflammatory Diseases, LeadDiscovery's unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today's bulletin click here

(Editorial note: In depth reports on rheumatoid arthritis can be found at LeadDiscovery's report center or click here for suggested reading on the treatment of rheumatoid arthritis)

LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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