RT Journal Article
T1 A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma.
A1 Haugaard-Kedström, Linda M
A1 Clemmensen, Louise S
A1 Sereikaite, Vita
A1 Jin, Zeyu
A1 Fernandes, Eduardo F A
A1 Wind, Bianca
A1 Abalde-Gil, Flor
A1 Daberger, Jan
A1 Vistrup-Parry, Maria
A1 Aguilar-Morante, Diana
A1 Leblanc, Raphael
A1 Egea-Jimenez, Antonio L
A1 Albrigtsen, Marte
A1 Jensen, Kamilla E
A1 Jensen, Thomas M T
A1 Ivarsson, Ylva
A1 Vincentelli, Renaud
A1 Hamerlik, Petra
A1 Andersen, Jeanette Hammer
A1 Zimmermann, Pascale
A1 Lee, Weontae
A1 Strømgaard, Kristian
AB 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.
YR 2021
FD 2021-01-27
LK https://hdl.handle.net/10668/26203
UL https://hdl.handle.net/10668/26203
LA en
DS RISalud
RD Apr 11, 2025