Targeting central regulation of oncogenic signaling through inhibition of translation initiation complex eIF4F

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Cancer is a widespread group of diseases with deleterious effects on society with regard to human health and financial burden. Furthermore, the development of chemoresistance to first-line therapies is responsible for the majority of deaths (over 90%) in tumor patients. Elevated protein synthesis is a critical trait that is associated with genesis, poor prognosis, and drug resistance in many types of human cancers. Eukaryotic initiation factor 4F (eIF4F), a cap-dependent mRNA translation initiation complex forms a central node for frequently upregulated oncogenic pathways such as Myc, Ras, and PI3K-AKT-mTOR. An essential requirement for the assembly and operation of the eIF4F translational machinery is the interaction between subunits eIF4E and eIF4G. Inhibition of this protein-protein interaction (PPI) has been recently demonstrated as a viable approach to target translation initiation. However, the published PPI inhibitors suffer from low affinity and solubility issues along with off-target effects. Thus, our goal is to develop novel drug-like and selective small molecule inhibitors of eIF4E/eIF4G interaction. Our hypothesis is that the canonical motif-binding site on the surface of eIF4E can be targeted via mimicry of eIF4G. Our computational approach identified novel scaffolds that could potentially inhibit this interaction by targeting the hot-spot residues on the surface of eIF4E. These compounds are devoid of PAINS characteristics and facilitate scanning of 3D space on the eIF4E surface. To test our hypothesis, we will pursue three specific aims. Aim 1 will focus on the design and synthesis of novel PPI inhibitors with drug-like properties. These synthesized compounds will be assessed in fluorescence polarization and pull-down assays to determine the eIF4E/eIF4G interaction inhibition profile in Aim 2. Aim 3 will evaluate the cellular effects by testing the high- affinity compounds in a dual luciferase assay. This assay enables the determination of inhibition of cap- dependent versus cap-independent translation. Further, the selected compounds will be tested for their anti- proliferative effects on human cancer cell lines.