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A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Permanent link
https://hdl.handle.net/10037/24505
DOI
https://doi.org/10.1021/acs.jmedchem.0c00382
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Accepted manuscript version (PDF)
Date
2021-01-27
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Author
Haugaard-Kedström, Linda M.; Clemmensen, Louise S.; Sereikaite, Vita; Jin, Zeyu; Fernandes, Eduardo F. A.; Wind, Bianca; Abalde-Gil, Flor; Daberger, Jan; Vistrup-Parry, Maria; Aguilar-Morante, Diana; Leblanc, Raphael; Egea-Jimenez, Antonio L.; Albrigtsen, Marte; Jensen, Kamilla E.; Jensen, Thomas M. T.; Ivarsson, Ylva; Vincentelli, Renaud; Hamerlik, Petra; Andersen, Jeanette Hammer; Zimmermann, Pascale; Lee, Weonate; Strømgaard, Kristian
Abstract
Despite 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.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © 2021 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.0c00382.
Publisher
American Chemical Society
Citation
Haugaard-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):1423-1434
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Copyright 2021 American Chemical Society

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