Class ADisease Specific

A disease specific molecular target should be a molecule that operates only in the disease state and is not participating in physiological (normal) functions. Drug interaction with such targets should provide efficacy with the lowest chance for mechanism-based adverse effects when manipulated by drugs. Examples of such targets are genetic disorders, which result in either over-activity or loss of activity of the target. Such is the case in Chronic Myelogenous Leukemia (CML) that results from aberrant recombination of DNA from chromosome 22 into chromosome 9 (Philadelphia Chromosome), fusing the Bcr and Abl genes into an overacting tyrosine kinase, which drives oncogenic transformation. To cure the disease, potent and selective inhibitors of this aberrant kinase had to be discovered, a task that took over a decade to accomplished.13 Such targets have the potential for a high safety profile. It is however, important to note that this example may does not necessarily represent the ultimate approach for this disease since the activity of the kinase (Bcr/Abl) is driven by the Abl kinase catalytic site, which is preserved in its physiological format. Thus, inhibitors of this target/kinase by drugs such as Gleevec may still carry the potential for interference with in tissue/cells where the Abl kinase is physiologically active.

Another example that is applicable to this category is a disease such as Myasthenia Gravis where specific antibodies that block the acetylcholine receptors cause progressive muscle weakness. Specific neutralizing agents to these antibodies are likely to provide high efficacy in treating the disease with the likelihood of fewer adverse effects14 since such antibodies are not physiologically present in human beings. These examples are typical for "Type 1 class A" target validation. The biomarkers that need to be established for this "Type 1 class A" category should focus on validating the specificity of the target to the disease state.

Class B—Target Present Physiologically but in a Non-Active Form, but Is Activated and Contributes to the Disease

This class of targets has little or no discernible physiological activity in the normal states, yet in certain pathophysiological situations, the target is presented, activated and plays a role in a

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