This project will develop ad hoc strategies for identifying the cellular targets of small-molecule inhibitors. More specifically, the program will address the mechanism of action of selected subsets of small molecules that have a recognized potential to eventually become drugs. We will operate therefore in a collaborative framework with the drug screening and medicinal chemistry programs at the IFOM-IEO Campus and the IIT Central Research Lab at Morego. From a technological perspective, the project will exploit a combination of cellular assays, classical biochemistry, medicinal chemistry, and large-scale proteomics and genomics analyses. Cellular resistance/sensitivity to drugs will be exploited as the main entry point for primary and secondary target identification.

A large fraction of known drugs are small organic molecules (molecular weight <500). Small molecules are identified from a large library of compounds through two main types of screens, based, respectively, on their ability to interfere with a known protein target (molecular-target based screens) or to revert a specific phenotype in a cell or a tissue (phenotype screens). Our focus on phenotype screens of important cellular pathways will feed into a cancer drug discovery program.

A necessary complement to the phenotype-screening program is a program for the identification and validation of targets. The main limitation of phenotypic screening programs based on small molecules resides in identifying the macromolecular targets of the small-molecule inhibitors that cause the phenotype.

We will tackle this issue following three approaches: