A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy

Publication type:
Journal article
Metadata:
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000611487200001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s10637-020-01042-w
eISSN
1573-0646
Externe Identifier
  • Clarivate Analytics Document Solution ID: TJ5FY
  • PubMed Identifier: 33492639
ISSN
0167-6997
Ausgabe der Veröffentlichung
4
Zeitschrift
INVESTIGATIONAL NEW DRUGS
Schlüsselwörter
  • Differentiation therapy
  • Molecular docking
  • Precision medicine
  • Targeted therapy
  • Virtual drug screening
Paginierung
914 - 927
Datum der Veröffentlichung
2021
Status
Published
Titel
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy
Sub types
  • Article
Ausgabe der Zeitschrift
39

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Summary</jats:title><jats:p><jats:italic>Introduction</jats:italic> Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. <jats:italic>Methods</jats:italic> Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The <jats:italic>in silico</jats:italic> results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. <jats:italic>Results</jats:italic> Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a K<jats:sub>D</jats:sub> of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. <jats:italic>Discussion</jats:italic> ZINC10157406 was identified as potent ligand of TCTP by <jats:italic>in silico</jats:italic> and <jats:italic>in vitro</jats:italic> methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.</jats:p>
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Thomas Efferth
DOI
10.1007/s10637-020-01042-w
eISSN
1573-0646
ISSN
0167-6997
Ausgabe der Veröffentlichung
4
Zeitschrift
Investigational New Drugs
Sprache
en
Online publication date
2021
Paginierung
914 - 927
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s10637-020-01042-w
Datum der Datenerfassung
2023
Titel
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy
Ausgabe der Zeitschrift
39

Data source: Crossref

Abstract
Introduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a K<sub>D</sub> of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.
Addresses
  • Department of Pharmaceutical Biology, Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Thomas Efferth
DOI
10.1007/s10637-020-01042-w
eISSN
1573-0646
Externe Identifier
  • PubMed Identifier: 33492639
  • PubMed Central ID: PMC8280061
Open access
true
ISSN
0167-6997
Ausgabe der Veröffentlichung
4
Zeitschrift
Investigational new drugs
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasms
  • Antineoplastic Agents
  • Drugs, Investigational
  • Ligands
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Computer Simulation
  • Cell Cycle Checkpoints
  • Databases, Pharmaceutical
  • Molecular Docking Simulation
  • Artesunate
  • Tumor Protein, Translationally-Controlled 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
914 - 927
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy.
Sub types
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
39

Files

https://link.springer.com/content/pdf/10.1007/s10637-020-01042-w.pdf https://europepmc.org/articles/PMC8280061?pdf=render

Data source: Europe PubMed Central

Abstract
Introduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.
Date of acceptance
2020
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33492639
DOI
10.1007/s10637-020-01042-w
eISSN
1573-0646
Externe Identifier
  • PubMed Central ID: PMC8280061
Ausgabe der Veröffentlichung
4
Zeitschrift
Invest New Drugs
Schlüsselwörter
  • Differentiation therapy
  • Molecular docking
  • Precision medicine
  • Targeted therapy
  • Virtual drug screening
  • Antineoplastic Agents
  • Artesunate
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Survival
  • Computer Simulation
  • Databases, Pharmaceutical
  • Dose-Response Relationship, Drug
  • Drugs, Investigational
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Neoplasms
  • Tumor Protein, Translationally-Controlled 1
Sprache
eng
Country
United States
Paginierung
914 - 927
PII
10.1007/s10637-020-01042-w
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy.
Sub types
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
39

Data source: PubMed

Author's licence
CC-BY
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Thomas Efferth
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
DOI
10.1007/s10637-020-01042-w
File(s) embargoed
false
Open access
true
ISSN
1573-0646
Zeitschrift
Investigational new drugs
Schlüsselwörter
  • 610 Medizin
  • 610 Medical sciences
Sprache
eng
Open access status
Open Access
Paginierung
914 - 927
Datum der Veröffentlichung
2021
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/7292
Herausgeber
Springer Science + Business Media B.V.
Datum der Datenerfassung
2022
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Zugang
Public
Titel
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy
Ausgabe der Zeitschrift
39

Files

a_novel_ligand_of_the_transla-20220701124103992.pdf

Data source: OPENSCIENCE.UB

Beziehungen:
Property of

Tools