INitiation FActor 3 as target in Cancer Therapy

Objetivo

Eukaryotic translation initiation is a process wherein ribosomal subunits are assembled by eukaryotic initiation factor (eIF) proteins. Mammalian eukaryotic translation initiation factor 3 (eIF3), consisting of the 13 subunits eIF3a to eIF3m, is the largest and most complex eIF. Due to the emerging understanding of the role of eIF3 in a wide range of cancers, there is an increasing interest to examine its many subunits as potential therapeutic targets. Furthermore, interactions between subunit eIF3c and tumor suppressor protein schwannomin has been reported to promote development of the tumor neurofibromatosis 2 (NF2). Very few small molecule inhibitors reported targeting eIF3 subunits are reported, and are associated with high degree of uncertainty. There is hence a need to develop new and highly effective small molecules targeting the eIF3 subunits to be used in the treatment of cancer, as well as in the fundamental understanding of the interactions between the various subunits.
The aim of this interdisciplinary project is to investigate the structures, dynamics, and interactions of subunits in the eIF3 family, and use this information to design, synthesize and test compounds for targeted cancer therapy. We will employ a range of computational and bioinformatics-based tools (protein-protein docking, molecular dynamics and metadynamics simulations, machine-learning based ligand design and docking techniques) to identify and explore key druggable interactions and regions in the initially targeted subunits eIF3a and c. To verify the inhibitory potential of the designed small molecules, chemical synthesis and in vitro evaluation will be performed. Through the combination of computational modeling, subunit-specific inhibition, and measurements of anticancer activity, we will be able to understand in more detail the mechanisms of action as well as interplay between different subunits, and the interactions between eIF3c and tumor suppressor protein schwannomin.