FOXO transcription factors control apoptosis, stress resistance and longevity in mammalian cells. Although the members of the FOXO family act as tumor suppressors in some cell types, emerging evidence suggests that FOXO3 also contributes to tumor stem cell renewal, immune suppression, metastases and chemotherapy resistance in certain cancer types. By a combined in silico / cell biological screening approach several small, drug-like compounds that interact with the DNA-binding domain of FOXO3 and efficiently inhibit its transcriptional activity have been identified. The main aim of this project is to define the structural basis for the interaction between compounds and FOXO3 by NMR spectroscopy, design and develop derivatives with improved properties regarding solubility and affinity, analyze compound-dependent inhibition of target recognition by FOXO3 in vitro and in vivo, study the effects of compounds on FOXO3-induced cancer cell survival in 3D cell culture and in vivo.

This project is a collaboration with the group of prof. Michael J. Ausserlechner from Medical University Innsbruck, Innsbruck, Austria, and it is funded by Czech Science Foundation (Project 17-33854L).

The crystal structure of the FOXO-DNA-binding domain bound to DNA (PDB 3L2C)