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dc.contributor.authorvan der Vlag, Ramon
dc.contributor.authorYagiz Unver, M
dc.contributor.authorFelicetti, Tommaso
dc.contributor.authorTwarda-Clapa, Aleksandra
dc.contributor.authorKassim, Fatima
dc.contributor.authorErmis, Cagdas
dc.contributor.authorNeochoritis, Constantinos G
dc.contributor.authorMusielak, Bogdan
dc.contributor.authorLabuzek, Beata
dc.contributor.authorDömling, Alexander
dc.contributor.authorHolak, Tad A
dc.contributor.authorHirsch, Anna K H
dc.date.accessioned2020-09-29T12:21:14Z
dc.date.available2020-09-29T12:21:14Z
dc.date.issued2019-12-12
dc.identifier.citationChemMedChem. 2020 Feb 17;15(4):370-375. doi: 10.1002/cmdc.201900574.en_US
dc.identifier.pmid31774938
dc.identifier.doi10.1002/cmdc.201900574
dc.identifier.urihttp://hdl.handle.net/10033/622490
dc.description.abstractInnovative and efficient hit-identification techniques are required to accelerate drug discovery. Protein-templated fragment ligations represent a promising strategy in early drug discovery, enabling the target to assemble and select its binders from a pool of building blocks. Development of new protein-templated reactions to access a larger structural diversity and expansion of the variety of targets to demonstrate the scope of the technique are of prime interest for medicinal chemists. Herein, we present our attempts to use a protein-templated reductive amination to target protein-protein interactions (PPIs), a challenging class of drug targets. We address a flexible pocket, which is difficult to achieve by structure-based drug design. After careful analysis we did not find one of the possible products in the kinetic target-guided synthesis (KTGS) approach, however subsequent synthesis and biochemical evaluation of each library member demonstrated that all the obtained molecules inhibit MDM2. The most potent library member (Ki =0.095 μm) identified is almost as active as Nutlin-3, a potent inhibitor of the p53-MDM2 PPI.en_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleOptimized Inhibitors of MDM2 via an Attempted Protein-Templated Reductive Amination.en_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.eissn1860-7187
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalChemMedChemen_US
dc.source.volume15
dc.source.issue4
dc.source.beginpage370
dc.source.endpage375
refterms.dateFOA2020-09-29T12:21:14Z
dc.source.journaltitleChemMedChem
dc.source.countryUnited States
dc.source.countryGermany


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