MITiC · Molecules Inhibiting Translation in Cancer cells

Molecules Inhibiting Translation in Cancer cells

While targeting Protein:Protein interactions has served as basis for the development of new drugs, RNA:Protein interactions, which are as important in human pathologies, notably cancer, is very promising but remains largely unexploited. Several challenges arise from the drug discovery process such as finding a druggable pocket in RNA-binding interfaces, the quality of the computational models, the strategies used in the in silico screening, and the lack of experimental feedback and validation of computationally predicted inhibitors essential to orient the rational drug design procedure toward the most relevant molecules. Besides the above listed issues, new experimental assays must be developed to screen molecules targeting RPIs which ideally would work in a cellular context and be amenable to high content screening (HCS). In this project, we address the lack of methods able to score RPIs in a cellular context by adapting the microtubule bench assay (MT bench) to score protein interactions with endogenous mRNAs in cells and implemented a robust HCS-based detection scheme. We have also developed a drug screening approach that integrates chemical, structural and cellular data from both advanced computational and experimental techniques for the development of small molecules that target RPIs. This is done by developing an innovative approach that would integrate a) molecular modeling data (Drug design, Molecular Dynamics and Free Energy Simulations using a sufficiently accurate computational model that is computationally efficient), b) NMR Spectroscopy data, c) together with an experimental validation in cells with a new HCS technology, “MT Bench”, that quantifies RNA:protein interactions at the single cell level. The major advantage is providing cellular and structural data to feed, with little delay, the computational approach to propose efficient and specific ligands that target translation regulation in vitro and in cancer cells. As an application, we chose to target YB-1 (YBX1 gene), a mRNA-binding protein relevant target in cancer, notably owing to its role in cancer resistance and cancer cell plasticity. YB-1 has been recently considered as a therapeutic target for the treatment of cancer and drug-resistant cancer.

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