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MAPK/ERK-kinase inhibition as a promising strategy

Target of the Month, TherapeuticAdvances, May, 200 Posted on: 26 Apr 03


Approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. The development of analgesics represe
Approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. One particular type of chronic pain, migraine is highlighted in the “Focus on Pain” section of our current edition of TherapeuticAdvances. More generally, the origins of pain range from nociceptive (caused by tissue injury or inflammation) to neuropathic, a condition that can have many underlying causes. Since chronic pain is notoriously difficult to treat using currently available therapeutics, the development of analgesics has represented a major pharmaceutical objective. (click here for "Pain 2002" an analysis of future directions in analgesic therapeutics).

Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments. This condition precipitates other serious conditions such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide. Due to the high incidence and the poor efficacy of current treatment for neuropathic pain, novel targets for this condition are being keenly sought. Of particular interest in this respect is a recent study conducted by researchers at Pfizer that identified changes in gene expression streptozocin induced diabetic neuropathy. Expression of several key components of the extracellular signal-regulated kinase (ERK) cascade was found to be altered. In particular, levels of ERK1 and 2 correlated with the onset of streptozocin-induced hyperalgesia. Establishing the ERK cascade as a therapeutic target this group demonstrated that intrathecal administration of the selective MAPK/ERK-kinase (MEK) inhibitor PD 198306 dose-dependently blocked static allodynia in both the streptozocin and the chronic constriction injury models of neuropathic pain. Since intraplantar administration of PD 198306 had no effect in either model of hyperalgesia, changes in the activation of ERKs and the effect of MEK inhibition are localized to the central nervous system.

This study clearly demonstrates the proof of concept supporting the development of MEK inhibitors for the treatment of neuropathic pain. To date few selective MEK inhibitors have been developed and further development in this field may lead to the identification of molecules with considerable therapeutic and commercial value. Readers who are interested in developing novel MEK inhibitors should be aware of the “Kinase Enterprise Library” that LeadDiscovery has recently featured. This is a targeted library of candidate kinase inhibitors that is available for in house screening. Alternatively, options are available through which LeadDiscovery’s partner ChemOvation can dock this library into the active site of MEK using their suite of computational tools (Click here for further information on this library).

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Adapted from Ciruela et al, Br J Pharmacol 2003 Mar;138(5):751-6.


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

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