DRUG TARGET VALIDATION AND IDENTIFICATION OF SECONDARY DRUG TARGET EFFECTS USING DNA MICROARRAYS

We describe here a method for drug target validation and identificatio n of secondary drug target effects based on genome-wide gene expressio n patterns. The method is demonstrated by several experiments, includi ng treatment of yeast mutant strains defective in calcineurin, immunop hilins or other genes with the immunosuppressants cyclosporin A or FK5 06. Presence or absence of the characteristic drug 'signature' pattern of altered gene expression in drug-treated cells with a mutation in t he gene encoding a putative target established whether that target was required to generate the drug signature. Drug dependent effects were seen in 'targetless' cells, showing that FK506 affects additional path ways independent of calcineurin and the immunophilins. The described m ethod permits the direct confirmation of drug targets and recognition of drug-dependent changes in gene expression that are modulated throug h pathways distinct from the drug's intended target. Such a method may prove useful in improving the efficiency of drug development programs .