We apply chemical biology approaches to identify novel compounds that target eukaryotic translation initiation and to which tumor cells appear particularly sensitive. We have identified a set of natural products that inhibit an RNA helicase, eIF4A, critical for the recruitment of ribosomes to mRNAs, characterized the mode of action of these molecules, and assessed their efficacy in pre-clinical cancer models. We currently have a Research Program to assess their effects on the translation footprint in different cancer cells, determine how they are capable of reversing drug resistance in certain settings, assessing their consequences on the tumor-host crosstalk and impact on tumor heterogeneity. We are also using CRISPR-Cas9 to establish phenotype-based high throughput screens for difficult to drug targets. Our current focus is c-MYC expression inhibitors but our gene tracing platform can be adapted to any expressed locus of interest in search for expression inhibitors. Finally, we are manipulating the organizing principles of translation. Using synthetic biology approaches, coupled with the RNA targeting capabilities of CRISPR-Cas9, we are developing new approaches by which to redirect the translation initiation apparatus to specific mRNAs and to pre-defined addresses on these templates. The ability to manipulate the gene expression pathway has unique advantages to treating genetic disorders.