1. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma
- Author
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Jan Daberger, Louise S. Clemmensen, Kristian Strømgaard, Eduardo Felipe Alves Fernandes, Flor Abalde-Gil, Weontae Lee, Pascale Zimmermann, Raphael Leblanc, Petra Hamerlik, Renaud Vincentelli, Jeanette Hammer Andersen, Zeyu Jin, Vita Sereikaite, Bianca Wind, Marte Albrigtsen, Thomas M. T. Jensen, Maria Vistrup-Parry, Antonio L. Egea-Jimenez, Diana Aguilar-Morante, Linda M. Haugaard-Kedström, Kamilla E. Jensen, Ylva Ivarsson, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Scaffold protein ,Models, Molecular ,Syntenins ,[SDV]Life Sciences [q-bio] ,PDZ domain ,Chemistry, Medicinal ,Antineoplastic Agents ,Plasma protein binding ,medicine.disease_cause ,Ligands ,01 natural sciences ,03 medical and health sciences ,Mice ,Drug Delivery Systems ,X-Ray Diffraction ,Cell Line, Tumor ,Microsomes ,Drug Discovery ,medicine ,Animals ,Humans ,Viability assay ,Pharmacology & Pharmacy ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Mutation ,Science & Technology ,Chemistry ,Brain Neoplasms ,Xenograft Model Antitumor Assays ,0104 chemical sciences ,Cell biology ,High-Throughput Screening Assays ,010404 medicinal & biomolecular chemistry ,Cell culture ,Molecular Medicine ,Glioblastoma ,Peptides ,Postsynaptic density ,Life Sciences & Biomedicine ,Intracellular ,Protein Binding - Abstract
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. 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.
- Published
- 2021