Identification of small molecules that interfere with the association between two nuclear factors
|Principal Investigator||Philippe Roux|
The interleukin enhancer binding factor 2 and 3 (ILF2 and ILF3) associate in cells to regulate different steps in gene expression, including transcription and translation. These proteins are overexpressed in several types of tumors, suggesting that they provide a proliferative advantage to cancer cells. Consistent with this, depletion of ILF2 and ILF3 was shown to inhibit cell cycle progression and the proliferation or various cancer cell lines. At a molecular level, ILF2 and ILF3 interact in cells to form a 1:1 heterodimer, and this association was found to involve their respective DZF domains (domain associated with zinc fingers). Depletion of ILF2 or ILF3 results in the loss of its binding partner, indicating that the interaction between ILF2 and ILF3 increases their protein stability. The main objective of this project is to identify small molecules that interfere with the ILF2:ILF3 complex and thereby inhibit its function. Such compounds would provide tools to acutely manipulate the ILF2:ILF3 complex, and thereby determine its exact role in cell cycle progression and cell proliferation. We propose to use an already optimized BRET-based assay to screen for compounds that inhibit the interaction between ILF2:ILF3. In parallel, we plan to take advantage of the crystal structure of the complex to perform an in silico screen for molecular docking. Hits coming out from both approaches will be validated using robust secondary assays on endogenous proteins, and structure-activity relationship studies will be performed on more promising molecular entities. Beyond this initial 12 months, our future plans will be to determine whether identified compounds affect cell cycle progression and cancer cell proliferation by modulating ILF2:ILF3 function.