Modulation of PDZ domain-mediated protein-protein interactions
Final Report Abstract
PDZ (PSD-95, Dlg, ZO-1) domains play important roles in cellular signaling pathways mediating protein–protein interactions by binding to the C-termini of target proteins, in most cases receptors and ion channels. Inhibitors with low to medium affinity for AF6, DVL and Shank3 PDZ domains were identified in the first funding period and collected in a „PDZ-library', together with further members of the respective substance classes and compounds identified by virtual screening of a representative set of PDZ domains. In the period from 2010 to 2013, improvements of PDZ-domain inhibitors by modellingchemistry cycles resulted in compounds with sufficient affinity to disrupt native PDZ interactions in cell lysates or cellular assays. In the course of this work, cycles of NMR screening of derivatives and modelling were applied to improve affinities and selectivity. In-vitro and in-vivo experiments with the AF6- specific ligands were completed and its role in Bcr-dependent signaling was analyzed. We developed further small-molecule ligands for the Dishevelled (DVL) and Shank3 PDZ domains, aiming at an understanding of the biology of the respective proteins. Inhibitors of DVL were investigated with respect to their effects on the Wnt signalling pathway in collaboration with TP 9 (Birchmeier, von Kries). In cooperation with TP1 (Klussmann, Rosenthal) small molecules have been designed as inhibitors for AKAP/ PKA interaction which were experimentally confirmed.
Publications
- (2011) Discovery, structure-activity relationship studies, and crystal structure of nonpeptide inhibitors bound to the Shank3 PDZ domain. ChemMedChem., 6(8), 1411-22
Saupe, J., Roske, Y., Schillinger, C., Kamdem, N., Radetzki, S., Diehl, A., Oschkinat, H., Krause, G., Heinemann, U., Rademann, J.
(See online at https://doi.org/10.1002/cmdc.201100094) - (2013) Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions. Angewandte Chemie Int. Ed., 52(46), 12187-91
Schäfer, G., Milić, J., Eldahshan, A., Götz, F., Zühlke, K., Schillinger, C., Kreuchwig, A., Elkins, J.M., Abdul, Azeez K.R., Oder, A., Moutty, M.C., Masada, N., Beerbaum, M., Schlegel, B., Niquet, S., Schmieder, P., Krause, G., von Kries, J.P., Cooper, D.M., Knapp, S., Rademann, J., Rosenthal, W., Klussmann, E.
(See online at https://doi.org/10.1002/anie.201304686) - (2014): Small-molecule inhibitors of AF6 PDZ-mediated protein-protein interactions. In: ChemMedChem 9 (7), S. 1458–1462
Vargas, C., Radziwill, G., Krause, G., Diehl, A., Keller, S., Kamdem, N., Czekelius, C., Kreuchwig, A., Schmieder, P., Doyle, D., Moelling, K., Hagen, V., Schade, M., Oschkinat, H.
(See online at https://doi.org/10.1002/cmdc.201300553)
