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Journal Article

Fragment-Based Library Generation for the Discovery of a Peptidomimetic p53-Mdm4 Inhibitor

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78902

Wolf,  Siglinde
Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78123

Holak,  Tad A.
Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Boltjes, A., Huang, Y., van de Velde, R., Rijkee, L., Wolf, S., Gaugler, J., et al. (2014). Fragment-Based Library Generation for the Discovery of a Peptidomimetic p53-Mdm4 Inhibitor. ACS COMBINATORIAL SCIENCE, 16(8), 393-396. doi:10.1021/co500026b.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0023-D9FB-3
Abstract
On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (K-i = 5 mu M, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.