Polypharmacology (action of drugs against multiple targets) represents a tempting avenue for new drug development; unfortunately, methods capable of exploiting the known polypharmacology of drugs for target deconvolution are lacking. Here, we present an ensemble approach using elastic net regularization combined with mRNA expression profiling and previously characterized data on a large set of kinase inhibitors to identify kinases that are important for epithelial and mesenchymal cell migration. By profiling a selected optimal set of 32 kinase inhibitors in a panel against six cell lines, we identified cell type-specific kinases that regulate cell migration. Our discovery of several informative kinases with a previously uncharacterized role in cell migration (such as Mst and Taok family of MAPK kinases in mesenchymal cells) may represent novel targets that warrant further investigation. Target deconvolution using our ensemble approach has the potential to aid in the rational design of more potent but less toxic drug combinations.systems pharmacology | regularized regression | perturbation biology | predictive modeling | cancer cell migration F or most diseases, the development of specific "one target, one drug" or euphemistically, "magic bullet" therapy, has been difficult to achieve (1). It is even rather difficult to chemically achieve single target specificity. Furthermore, it is now evident that many of the most effective drugs in therapeutic areas as diverse as oncology (such as Gleevec), psychiatry (such as serotonin reuptake inhibitors), and inflammation (such as aspirin) act on multiple rather than single targets-a phenomenon known as polypharmacology (2, 3). Although the pharmaceutical industry and the US Food and Drug Administration (FDA) has for years focused on single targets, it may turn out to be true that hitting multiple targets is preferable, an emerging idea referred to as network pharmacology.Designing drugs with a specific multitarget profile or designing a rational combination of such drugs is both complex and difficult, but could serve to improve the balance between efficacy and safety compared with single targets agents. Therefore, despite the complexity of designing such drugs, there is an incentive to develop new systems-based methods capable of exploiting the known polypharmacology of drugs to identify the molecular targets of active hits, also called "target deconvolution." Such methods are not only important for elucidating mechanisms of action but also for identifying effective pathways involved in disease as a preliminary step in rational design of drugs for new targets. Furthermore, if target-specific toxicity and off-target effects could be addressed early in the drug discovery pipeline, the high attrition rate in drug development might be reduced (4).Recent advances in high-throughput "omics" technologies have led to the development of methods to efficiently and reliably profile drug target selectivities both in vitro and in the cellular environment. One such well-characterized s...