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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-D9FB-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-D9FC-1
Genre: Journal Article

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 Creators:
Boltjes, Andre1, Author
Huang, Yijun1, Author
van de Velde, Rob1, Author
Rijkee, Laurie1, Author
Wolf, Siglinde2, Author              
Gaugler, James1, Author
Lesniak, Katarzyna1, Author
Guzik, Katarzyna1, Author
Holak, Tad A.2, Author              
Dömling, Alexander1, Author
Affiliations:
1external, ou_persistent22              
2Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              

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Free keywords: LEAD COMPOUNDS; MDMX; ANTAGONISTS; P53; PROTEINSpeptidomimetic p53-Mdm4 inhibitor; Ugi four-component reaction; library generation;
 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.

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Language(s): eng - English
 Dates: 2014-08
 Publication Status: Published in print
 Pages: 4
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000340344500004
DOI: 10.1021/co500026b
 Degree: -

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Title: ACS COMBINATORIAL SCIENCE
Source Genre: Journal
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Affiliations:
Publ. Info: 1155 16TH ST, NW, WASHINGTON, DC 20036 USA : AMER CHEMICAL SOC
Pages: - Volume / Issue: 16 (8) Sequence Number: - Start / End Page: 393 - 396 Identifier: ISSN: 2156-8952