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dc.contributor.authorJung, Kwan-Young
dc.contributor.authorWang, Huabo
dc.contributor.authorTeriete, Peter
dc.contributor.authorYap, Jeremy L
dc.contributor.authorChen, Lijia
dc.contributor.authorLanning, Maryanna E
dc.contributor.authorHu, Angela
dc.contributor.authorLambert, Lester J
dc.contributor.authorHolien, Toril
dc.contributor.authorSundan, Anders
dc.contributor.authorCosford, Nicholas D P
dc.contributor.authorProchownik, Edward V
dc.contributor.authorFletcher, Steven
dc.date.accessioned2017-12-12T09:23:51Z
dc.date.available2017-12-12T09:23:51Z
dc.date.created2015-07-13T12:55:50Z
dc.date.issued2015
dc.identifier.citationJournal of Medicinal Chemistry. 2015, 58 (7), 3002-3024.nb_NO
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/11250/2470572
dc.description.abstractThe rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic α-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer’s binding to its canonical E-box DNA sequence without causing protein–protein dissociation, heralding a new mechanistic class of “direct” c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc–Max heterodimers over Max–Max homodimers with IC50 values as low as 5.6 μM. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc–Max heterodimers remained intact.nb_NO
dc.language.isoengnb_NO
dc.publisherAmerican Chemical Societynb_NO
dc.titlePerturbation of the c-Myc-Max Protein-Protein Interaction via Synthetic α-Helix Mimeticsnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionacceptedVersionnb_NO
dc.source.pagenumber3002-3024nb_NO
dc.source.volume58nb_NO
dc.source.journalJournal of Medicinal Chemistrynb_NO
dc.source.issue7nb_NO
dc.identifier.doi10.1021/jm501440q
dc.identifier.cristin1253664
dc.relation.projectStiftelsen Kristian Gerhard Jebsen: SKGJ-MED-007nb_NO
dc.relation.projectNorges forskningsråd: 223255nb_NO
dc.relation.projectKreftforeningen: 2215992nb_NO
dc.description.localcode© 2015 American Chemical Society.This document is the Accepted Manuscript version of a Published Work that appeared in final form after peer review and technical editing by the publisher. To access the final edited and published work see dx.doi.org/10.1021/jm501440qnb_NO
cristin.unitcode194,65,15,0
cristin.unitnameInstitutt for klinisk og molekylær medisin
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2


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