الفهرس 
Introduction
MaterialsOnly 14 pages are availabe for public view
 |  | from | 144 |  |  |
| | | from | 144 | | |
Abstract
Aberrant Wnt/Beta-Catenin signaling is observed in a wide spectrum of human malignancies. Activation of this pathway is involved in colon and ovarian cancer. Therefore, inhibitors of the TCF4/Beta-Catenin interaction are of great potential as antitumor agents. We used the recently described protein meta-structure approach to identify novel small molecule compounds as binders for Beta-Catenin. The identified ligands have been tested for binding with the target protein using 1D 1H-STD, 1D AFP NOESY, 2D NOESY and 19F-NMR. The identified binders were demonstrated to compete with the authentic Beta-Catenin binding partner TCF4. In addition, a dynamic combinatorial library has been designed to synthesize new ligands for Beta-Catenin. Moreover, 2D & 3D-NMR experiments were used to assign the backbone signals of full length TCF4 and two different truncations at different pH values. The data obtained from assignment at pH=4.5 and pH=2 were compared with the predicted random coil shifts. Secondary structure propensities were also compared which allowed us to estimate changes in secondary structure propensities upon pH change. Finally, further structural insight into the TCF4/Beta-Catenin complex was provided by a combined X-ray crystallography and NMR study employing selective lysine reductive-methylation reaction. To highlight the importance of our work, the resulting prospects for the development of new powerful anticancer drugs with a high safety profile will also be discussed.