Target validation.

Abstract

With the publication of draft maps of the human genome and an interim agreement that the human genome comprises approximately 21000 genes, there has been considerable anticipation that many novel disease-specific molecular targets will be rapidly identified and that these will form the basis of many new drug discovery programs. Genes associated with a given disease can thus be identified using genotyping and microarray approaches. However, transitioning from the identification to the subsequent validation and prioritization of their cognate proteins as bona fide drug targets using proteomic techniques--a process that could appropriately be termed targetomics--is still very much in its infancy, with expectations far exceeding present capabilities. The criteria for target validation have yet to be determined and the timing to success has been underestimated. Integrated pharmacological approaches that involve the use of the traditional null hypothesis approach and statistically validated replication have been largely overlooked in the enthusiasm to be the first to find new targets. Inevitably, the only useful measure of target validation occurs when a drug-like molecule, selective for the identified target, is advanced to the clinic where it can be shown to be efficacious in the appropriate human disease state.