Discovery of Small Compounds that Target FOXO Transcription Factors and Modulate their Transcriptional Activity and Physiological Function | Chapter 5 |New Innovations in Chemistry and Biochemistry Vol. 4

 FOXO transcription factors are important cell homeostasis regulators that regulate a wide range of target genes, guiding cell death, differentiation, longevity, and senescence in mammalian cells. The goal of this research was to find new chemical compounds that attach to FOXO3's DNA-binding domain and regulate its transcriptional activity. The plan was to combine in silico compound screening based on pharmacophore modelling with fluorescence polarisation protein-DNA binding tests and cell-based compound confirmation. Small compounds that physically interact with the DNA-binding domain (DBD) of FOXO transcription factors with the highest affinity for human FOXO3 were found using this method. These chemicals alter the FOXO3 transcriptional pathway in human cells rather than acting as pharmacologic inhibitors. NMR spectroscopy and docking experiments were used to determine the manner of interaction between drugs and the FOXO3-DBD. We show that substance S9 and its oxalate salt S9OX inhibit FOXO3 target promoter binding, modify gene transcription, and interfere with the physiological programme activated by FOXO3 in cancer cells. These tiny compounds demonstrate the druggability of the FOXO-DBD and give a structural basis for modifying these key homeostasis regulators in normal and malignant cells by directly changing protein-DNA interaction.

Author (S) Details

Judith Hagenbuchner
Department of Pediatrics II, Medical University Innsbruck, Innrain 66, Innsbruck, Austria.

Veronika Obsilova
Department of Structural Biology of Signaling Proteins, Institute of Physiology, Division BIOCEV, The Czech Academy of Sciences, Prague 14220, Czech Republic.

Petra Obexer
Department of Pediatrics II, Medical University Innsbruck, Innrain 66, Innsbruck, Austria.

Tomas Obsil
Department of Structural Biology of Signaling Proteins, Institute of Physiology, Division BIOCEV, The Czech Academy of Sciences, Prague 14220, Czech Republic and Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague 12843, Czech Republic.

Michael J. Ausserlechner
Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria.

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