A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

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Standard

A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. / Haugaard-Kedstrom, 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, Weontae; Stromgaard, Kristian.

I: Journal of Medicinal Chemistry, Bind 64, Nr. 3, 2021, s. 1423-1434.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Haugaard-Kedstrom, LM, Clemmensen, LS, Sereikaite, V, Jin, Z, Fernandes, EFA, Wind, B, Abalde-Gil, F, Daberger, J, Vistrup-Parry, M, Aguilar-Morante, D, Leblanc, R, Egea-Jimenez, AL, Albrigtsen, M, Jensen, KE, Jensen, TMT, Ivarsson, Y, Vincentelli, R, Hamerlik, P, Andersen, JH, Zimmermann, P, Lee, W & Stromgaard, K 2021, 'A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma', Journal of Medicinal Chemistry, bind 64, nr. 3, s. 1423-1434. https://doi.org/10.1021/acs.jmedchem.0c00382

APA

Haugaard-Kedstrom, L. M., Clemmensen, L. S., Sereikaite, V., Jin, Z., Fernandes, E. F. A., Wind, B., Abalde-Gil, F., Daberger, J., Vistrup-Parry, M., Aguilar-Morante, D., Leblanc, R., Egea-Jimenez, A. L., Albrigtsen, M., Jensen, K. E., Jensen, T. M. T., Ivarsson, Y., Vincentelli, R., Hamerlik, P., Andersen, J. H., ... Stromgaard, K. (2021). A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. Journal of Medicinal Chemistry, 64(3), 1423-1434. https://doi.org/10.1021/acs.jmedchem.0c00382

Vancouver

Haugaard-Kedstrom LM, Clemmensen LS, Sereikaite V, Jin Z, Fernandes EFA, Wind B o.a. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. Journal of Medicinal Chemistry. 2021;64(3):1423-1434. https://doi.org/10.1021/acs.jmedchem.0c00382

Author

Haugaard-Kedstrom, 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, Weontae ; Stromgaard, Kristian. / A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. I: Journal of Medicinal Chemistry. 2021 ; Bind 64, Nr. 3. s. 1423-1434.

Bibtex

@article{52a7c8e473d3474fb4db2332d471117b,
title = "A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma",
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/discslarge/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 KSL128114 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.",
author = "Haugaard-Kedstrom, {Linda M.} and Clemmensen, {Louise S.} and Vita Sereikaite and Zeyu Jin and Fernandes, {Eduardo F. A.} and Bianca Wind and Flor Abalde-Gil and Jan Daberger and Maria Vistrup-Parry and Diana Aguilar-Morante and Raphael Leblanc and Egea-Jimenez, {Antonio L.} and Marte Albrigtsen and Jensen, {Kamilla E.} and Jensen, {Thomas M. T.} and Ylva Ivarsson and Renaud Vincentelli and Petra Hamerlik and Andersen, {Jeanette Hammer} and Pascale Zimmermann and Weontae Lee and Kristian Stromgaard",
year = "2021",
doi = "10.1021/acs.jmedchem.0c00382",
language = "English",
volume = "64",
pages = "1423--1434",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

RIS

TY - JOUR

T1 - A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

AU - Haugaard-Kedstrom, Linda M.

AU - Clemmensen, Louise S.

AU - Sereikaite, Vita

AU - Jin, Zeyu

AU - Fernandes, Eduardo F. A.

AU - Wind, Bianca

AU - Abalde-Gil, Flor

AU - Daberger, Jan

AU - Vistrup-Parry, Maria

AU - Aguilar-Morante, Diana

AU - Leblanc, Raphael

AU - Egea-Jimenez, Antonio L.

AU - Albrigtsen, Marte

AU - Jensen, Kamilla E.

AU - Jensen, Thomas M. T.

AU - Ivarsson, Ylva

AU - Vincentelli, Renaud

AU - Hamerlik, Petra

AU - Andersen, Jeanette Hammer

AU - Zimmermann, Pascale

AU - Lee, Weontae

AU - Stromgaard, Kristian

PY - 2021

Y1 - 2021

N2 - 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/discslarge/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 KSL128114 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.

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/discslarge/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 KSL128114 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.

U2 - 10.1021/acs.jmedchem.0c00382

DO - 10.1021/acs.jmedchem.0c00382

M3 - Journal article

C2 - 33502198

VL - 64

SP - 1423

EP - 1434

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -

ID: 261218225