| Conventional drug discovery and development is centered on a paradigm in which “validated” targets are subjected to in vitro screens for the identification of new drug candidates. Molecular profiling using genomic approaches is becoming an important complement to this process, and may eventually become a new paradigm for drug discovery that is based on monitoring critical pathway activity using complex biomarker sets. We have developed a high-throughput transcriptional screening system to monitor genomic response profiles within living cells for the identification of modulators of important pathways. This approach allows a universal, straightforward method to design a screen essentially any target or pathway, and to optimize the activity of the identified compounds. We have used this system to identify and describe the mechanisms of inhibitors of both the Beta catenin and Aurora pathways. Lead optimization and biomarker development in both programs will be described. |