Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor

2014
journal article
article
18
dc.abstract.enOn 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 (Ki = 5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.pl
dc.affiliationWydział Chemii : Zakład Chemii Organicznejpl
dc.contributor.authorBoltjes, Andrépl
dc.contributor.authorHaung, Yijunpl
dc.contributor.authorVan De Velde, Robpl
dc.contributor.authorRijkee, Lauriepl
dc.contributor.authorWolf, Siglindepl
dc.contributor.authorGaugler, Jamespl
dc.contributor.authorKubica, Katarzyna - 154222 pl
dc.contributor.authorGuzik, Katarzyna - 151366 pl
dc.contributor.authorHolak, Tadeusz - 214380 pl
dc.contributor.authorDömling, Alexanderpl
dc.date.accessioned2015-06-23T10:00:54Z
dc.date.available2015-06-23T10:00:54Z
dc.date.issued2014pl
dc.description.additionalNa publikacji autorka Kubica Katarzyna podpisana jako Leśniak Katarzyna. Na publikacji autor podpisany: Tad A. Holak. Katarzyna Guzik, Katarzyna Leśniak - Wydział Chemii UJ.pl
dc.description.number8pl
dc.description.physical393-396pl
dc.description.volume16pl
dc.identifier.doi10.1021/co500026bpl
dc.identifier.eissn2156-8944pl
dc.identifier.issn2156-8952pl
dc.identifier.urihttp://ruj.uj.edu.pl/xmlui/handle/item/10089
dc.languageengpl
dc.language.containerengpl
dc.rights.licencebez licencji
dc.subject.enpeptidomimetic p53-Mdm4 inhibitorpl
dc.subject.enlibrary generationpl
dc.subject.enUgi four-component reactionpl
dc.subtypeArticlepl
dc.titleFragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitorpl
dc.title.journalACS Combinatorial Sciencepl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
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 (Ki = 5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.
dc.affiliationpl
Wydział Chemii : Zakład Chemii Organicznej
dc.contributor.authorpl
Boltjes, André
dc.contributor.authorpl
Haung, Yijun
dc.contributor.authorpl
Van De Velde, Rob
dc.contributor.authorpl
Rijkee, Laurie
dc.contributor.authorpl
Wolf, Siglinde
dc.contributor.authorpl
Gaugler, James
dc.contributor.authorpl
Kubica, Katarzyna - 154222
dc.contributor.authorpl
Guzik, Katarzyna - 151366
dc.contributor.authorpl
Holak, Tadeusz - 214380
dc.contributor.authorpl
Dömling, Alexander
dc.date.accessioned
2015-06-23T10:00:54Z
dc.date.available
2015-06-23T10:00:54Z
dc.date.issuedpl
2014
dc.description.additionalpl
Na publikacji autorka Kubica Katarzyna podpisana jako Leśniak Katarzyna. Na publikacji autor podpisany: Tad A. Holak. Katarzyna Guzik, Katarzyna Leśniak - Wydział Chemii UJ.
dc.description.numberpl
8
dc.description.physicalpl
393-396
dc.description.volumepl
16
dc.identifier.doipl
10.1021/co500026b
dc.identifier.eissnpl
2156-8944
dc.identifier.issnpl
2156-8952
dc.identifier.uri
http://ruj.uj.edu.pl/xmlui/handle/item/10089
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights.licence
bez licencji
dc.subject.enpl
peptidomimetic p53-Mdm4 inhibitor
dc.subject.enpl
library generation
dc.subject.enpl
Ugi four-component reaction
dc.subtypepl
Article
dc.titlepl
Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor
dc.title.journalpl
ACS Combinatorial Science
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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