RNAi-induced inhibition of beta-catenin or Aurora kinase is associated with specific changes in gene expression in treated cells. Biomarker-driven drug discovery is a systems biology approach that uses such changes in gene expression as screening signatures to identify small molecule inhibitors of these same targets. We have successfully completed independent screens of small molecule libraries against beta-catenin and Aurora kinase signatures using this approach and have discovered a number of active compound families. We have systematically analyzed these hit compounds with a number of relevant secondary assays, in order to identify the most promising candidates from each program for lead selection and optimization. We will demonstrate that this discovery approach yields hit compounds that can inhibit multiple, distinct nodes within each pathway.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]