Modulating FOXO3 Transcriptional Activity by Small, DBD-binding Molecules
K. Kohoutova1,4, V. Docekal2, J. Vesely2, M. J. Ausserlechner3, V. Obsilova4, T. Obsil1
1Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2, 12843
2Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2, 12843
3Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria
4Department of Structural Biology of Signaling Proteins, Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic
kohoutk6@natur.cuni.cz
FOXO3 is a member of FOXO Transcription Factor family. FOXO proteins share a conserved DNA-binding motif called winged-helix DNA-binding domain (DBD). FOXO3 recognizes specific DNA sequence. Thourgh interaction with target DNA it modulates various biological processes, such as cell death, cell-cycle arrest, DNA repair and energy homeostasis [1]. Due to its ability to induce cell cycle arrest it is considered a tumor suppressor. However, in certain cases, it has been shown that FOXO3 promotes tumor development and angiogenesis via maintaining cancer cell energy homeostasis. FOXO3 can also enhance tumor cell resistence to chemoterapeutic agents [2]. Therefore, targeting of FOXO3 transcriptional activities by specific inhibitors can help to prevent drug resistance in cancer therapy.
A pharmacophore screening identified a small molecule compound that physically interacts with the FOXO3-DBD and modulates the FOXO3 transcriptional program in human cells. The mode of interaction between this compound and the FOXO3-DBD was characterized by NMR spectroscopy and docking studies [3]. This compound was further modified to increase its inhibitory potency. In this work we tested a group of newly designed inhibitors of FOXO3 transcriptional activity. Their inhibitory potency and interaction with FOXO3-DBD was tested using NMR and native electrophoresis. Furthermore, the effect of these compounds on FOXO3 transcriptional activity was evaluated in cell cultures. We have shown that these new derivatives are able not only to bind to FOXO3-DBD but also to inhibit its interaction with the target DNA.
Figure 1 – Graphical scheme of abstract
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