Protein-protein interactions (PPIs) are at the core of regulation mechanisms in biological systems and consequently became an attractive target for therapeutic intervention. PPIs involving the adapter protein 14-3-3 are representative examples given the broad range of partner proteins forming a complex with one of its seven human isoforms. Given the challenges represented by the nature of these interactions, fragment-based approaches offer a valid alternative for the development of PPI modulators. After having assembled a fragment set tailored on PPIs' modulation, we started a screening campaign on the sigma isoform of 14-3-3 adapter proteins. Through the use of both mono- and bi-dimensional nuclear magnetic resonance spectroscopy measurements, coupled with differential scanning fluorimetry, three fragment hits were identified. These molecules bind the protein at two different regions distant from the usual binding groove highlighting new possibilities for selective modulation of 14-3-3 complexes.

Department of Biomedical Engineering and Institute for Complex Molecular Systems Technische Universiteit Eindhoven Den Dolech 2 5612 AZ Eindhoven The Netherlands Email

Department of Chemistry University of Duisburg Essen Universitätsstraße 7 45117 Essen Germany

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University 12843 Prague Czech Republic

Department of Structural Biology of Signaling Proteins Division BIOCEV Institute of Physiology of the Czech Academy of Sciences Prumyslova 595 252 50 Vestec Czech Republic

Medicinal Chemistry Taros Chemicals GmbH and Co KG Emil Figge Straße 76a 44227 Dortmund Germany Email

Univ Lille CNRS UMR 8576 UGSF F 59000 Lille France Email

Zobrazit více v PubMed

Obsil T., Obsilova V. Semin. Cell Dev. Biol. 2011;22:663–672. PubMed

Daly R. J., Gu H., Parmar J., Malaney S., Lyons R. J., Kairouz R., Head D. R., Henshall S. M., Neel B. G., Sutherland R. L. Oncogene. 2002;21:5175–5181. PubMed

Aguilera C., Fernández-Majada V., Inglés-Esteve J., Rodilla V., Bigas A., Espinosa L. J. Cell Sci. 2006;119:3695–3704. PubMed

Masters S. C., Yang H., Datta S. R., Greenberg M. E., Fu H. Mol. Pharmacol. 2001;60:1325–1331. PubMed

Vousden K. H., Prives C. Cell. 2009;137:413–431. PubMed

Sluchanko N. N., Gusev N. B. J. Alzheimer's Dis. 2011;27:467–476. PubMed

Milroy L.-G., Grossmann T. N., Hennig S., Brunsveld L., Ottmann C. Chem. Rev. 2014;114:4695–4748. PubMed

Wuo M. G., Mahon A. B., Arora P. S. J. Am. Chem. Soc. 2015;137:11618–11621. PubMed PMC

Schumacher B., Mondry J., Thiel P., Weyand M., Ottmann C. FEBS Lett. 2010;584:1443–1448. PubMed

Valenti D., Hristeva S., Tzalis D., Ottmann C. Eur. J. Med. Chem. 2019;167:76–95. PubMed

Turnbull A. P., Boyd S. M., Walse B. Res. Rep. Biochem. 2014;4:13–26.

Valkov E., Sharpe T., Marsh M., Greive S., Hyvönen M. Top. Curr. Chem. 2012;317:145–179. PubMed

Magee T. V. Bioorg. Med. Chem. Lett. 2015;25:2461–2468. PubMed

Congreve M., Carr R., Murray C., Jhoti H. Drug Discovery Today. 2003;8:876–877. PubMed

Williamson M. P. Prog. Nucl. Magn. Reson. Spectrosc. 2013;73:1–16. PubMed

Unione L., Galante S., Díaz D., Cañada F. J., Jiménez-Barbero J. MedChemComm. 2014;5:1280–1289.

Gossert A. D., Jahnke W. Prog. Nucl. Magn. Reson. Spectrosc. 2016;97:82–125. PubMed

Sijbesma E., Hallenbeck K. K., Leysen S., de Vink P. J., Skóra L., Jahnke W., Brunsveld L., Arkin M. R., Ottmann C. J. Am. Chem. Soc. 2019;141:3524–3531. PubMed

Sijbesma E., Skora L., Leysen S., Brunsveld L., Koch U., Nussbaumer P., Jahnke W., Ottmann C. Biochemistry. 2017;56:3972–3982. PubMed PMC

Andrei S. A., Meijer F. A., Neves J. F., Brunsveld L., Landrieu I., Ottmann C., Milroy L.-G. ACS Chem. Neurosci. 2018;9:2639–2654. PubMed PMC

Milroy L.-G., Bartel M., Henen M. A., Leysen S., Adriaans J. M. C., Brunsveld L., Landrieu I., Ottmann C. Angew. Chem., Int. Ed. 2015;54:15720–15724. PubMed

Andrei S. A., de Vink P., Sijbesma E., Han L., Brunsveld L., Kato N., Ottmann C., Higuchi Y. Angew. Chem., Int. Ed. 2018;57:13470–13474. PubMed

Bier D., Rose R., Bravo-Rodriguez K., Bartel M., Ramirez-Anguita J. M., Dutt S., Wilch C., Klärner F.-G., Sanchez-Garcia E., Schrader T., Ottmann C. Nat. Chem. 2013;5:234–239. PubMed

Bier D., Mittal S., Bravo-Rodriguez K., Sowislok A., Guillory X., Briels J., Heid C., Bartel M., Wettig B., Brunsveld L., Sanchez-Garcia E., Schrader T., Ottmann C. J. Am. Chem. Soc. 2017;139:16256–16263. doi: 10.1021/jacs.7b07939. PubMed DOI PMC

Lovering F., Bikker J., Humblet C. J. Med. Chem. 2009;52:6752–6756. PubMed

Morley A. D., Pugliese A., Birchall K., Bower J., Brennan P., Brown N., Chapman T., Drysdale M., Gilbert I. H., Hoelder S., Jordan A., Ley S. V., Merritt A., Miller D., Swarbrick M. E., Wyatt P. G. Drug Discovery Today. 2013;18:1221–1227. PubMed

Neves J. F., Landrieu I., Merzougui H., Boll E., Hanoulle X., Cantrelle F.-X. Biomol. NMR Assignments. 2019;13:103–107. doi: 10.1007/s12104-018-9860-1. PubMed DOI

Dalvit C., Fogliatto G., Stewart A., Veronesi M., Stockman B. J. Biomol. NMR. 2001;21:349–359. PubMed

Ciulli A., in Protein-Ligand Interactions: Methods and Applications, ed. M. A. Williams and T. Daviter, Humana Press, Totowa, NJ, 2013, pp. 357–388.

Ma R., Wang P., Wu J., Ruan K. Molecules. 2016;21:854. PubMed PMC

Latham M. P., Zimmermann G. R., Pardi A. J. Am. Chem. Soc. 2009;131:5052–5053. PubMed PMC

Chen J., Hubbard R. E. J. Comput.-Aided Mol. Des. 2009;23:603–620. PubMed

Alblova M., Smidova A., Docekal V., Vesely J., Herman P., Obsilova V., Obsil T. Proc. Natl. Acad. Sci. U. S. A. 2017;114:E9811–E9820. PubMed PMC

Obsil T., Ghirlando R., Klein D. C., Ganguly S., Dyda F. Cell. 2001;105:257–267. PubMed

Ottmann C., Marco S., Jaspert N., Marcon C., Schauer N., Weyand M., Vandermeeren C., Duby G., Boutry M., Wittinghofer A., Rigaud J.-L., Oecking C. Mol. Cell. 2007;25:427–440. PubMed

Psenakova K., Petrvalska O., Kylarova S., Lentini Santo D., Kalabova D., Herman P., Obsilova V., Obsil T. Biochim. Biophys. Acta, Gen. Subj. 2018;1862:1612–1625. PubMed

Sluchanko N. N., Beelen S., Kulikova A. A., Weeks S. D., Antson A. A., Gusev N. B., Strelkov S. V. Structure. 2017;25:305–316. PubMed PMC

Taoka K., Ohki I., Tsuji H., Furuita K., Hayashi K., Yanase T., Yamaguchi M., Nakashima C., Purwestri Y. A., Tamaki S., Ogaki Y., Shimada C., Nakagawa A., Kojima C., Shimamoto K. Nature. 2011;476:332–335. PubMed