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dc.contributor.authorHaugaard-Kedström, Linda M.
dc.contributor.authorClemmensen, Louise S.
dc.contributor.authorSereikaite, Vita
dc.contributor.authorJin, Zeyu
dc.contributor.authorFernandes, Eduardo F. A.
dc.contributor.authorWind, Bianca
dc.contributor.authorAbalde-Gil, Flor
dc.contributor.authorDaberger, Jan
dc.contributor.authorVistrup-Parry, Maria
dc.contributor.authorAguilar-Morante, Diana
dc.contributor.authorLeblanc, Raphael
dc.contributor.authorEgea-Jimenez, Antonio L.
dc.contributor.authorAlbrigtsen, Marte
dc.contributor.authorJensen, Kamilla E.
dc.contributor.authorJensen, Thomas M. T.
dc.contributor.authorIvarsson, Ylva
dc.contributor.authorVincentelli, Renaud
dc.contributor.authorHamerlik, Petra
dc.contributor.authorAndersen, Jeanette Hammer
dc.contributor.authorZimmermann, Pascale
dc.contributor.authorLee, Weonate
dc.contributor.authorStrømgaard, Kristian
dc.date.accessioned2022-03-23T09:52:37Z
dc.date.available2022-03-23T09:52:37Z
dc.date.issued2021-01-27
dc.description.abstractDespite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.en_US
dc.descriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in the <i>Journal of Medicinal Chemistry</i>, copyright © 2021 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see <a href=https://doi.org/10.1021/acs.jmedchem.0c00382>https://doi.org/10.1021/acs.jmedchem.0c00382</a>.en_US
dc.identifier.citationHaugaard-Kedström LM, Clemmensen, Sereikaite, Jin, Fernandes, Wind, Abalde-Gil, Daberger, Vistrup-Parry, Aguilar-Morante, Leblanc, Egea-Jimenez, Albrigtsen, Jensen, Jensen, Ivarsson Y, Vincentelli R, Hamerlik, Andersen JH, Zimmermann P, Lee, Strømgaard. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. Journal of Medicinal Chemistry. 2021;64(3):1423-1434en_US
dc.identifier.cristinIDFRIDAID 1932901
dc.identifier.doi10.1021/acs.jmedchem.0c00382
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.urihttps://hdl.handle.net/10037/24505
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.journalJournal of Medicinal Chemistry
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 American Chemical Societyen_US
dc.titleA High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastomaen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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