2. Academic Validation
  3. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

  • J Med Chem. 2021 Feb 11;64(3):1423-1434. doi: 10.1021/acs.jmedchem.0c00382.
Linda M Haugaard-Kedström 1,  Louise S Clemmensen 1,  Vita Sereikaite 1,  Zeyu Jin 2,  Eduardo F A Fernandes 1,  Bianca Wind 1,  Flor Abalde-Gil 1,  Jan Daberger 1,  Maria Vistrup-Parry 1,  Diana Aguilar-Morante 3,  Raphael Leblanc 4,  Antonio L Egea-Jimenez 4 5,  Marte Albrigtsen 6,  Kamilla E Jensen 3,  Thomas M T Jensen 1,  Ylva Ivarsson 7,  Renaud Vincentelli 8,  Petra Hamerlik 3,  Jeanette Hammer Andersen 6,  Pascale Zimmermann 4 5,  Weontae Lee 2,  Kristian Strømgaard 1
Affiliations

Affiliations

  • 1 Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • 2 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 120-749 Seoul, Korea.
  • 3 Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
  • 4 Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.
  • 5 Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
  • 6 Marbio, UiT-The Artic University of Norway, N-9037 Tromsø, Norway.
  • 7 Department of Chemistry-BMC, Uppsala University, SE-751 23 Uppsala, Sweden.
  • 8 Unité Mixte de Recherche (UMR) 7257, Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB), Campus de Luminy, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
PMID: 33502198 DOI: 10.1021/acs.jmedchem.0c00382
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10331
    Syntenin Peptide Inhibitor