AMG900 as novel inhibitor of the translationally controlled tumor protein

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000608779400006&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.cbi.2020.109349
eISSN
1872-7786
Externe Identifier
  • Clarivate Analytics Document Solution ID: PT7GG
  • PubMed Identifier: 33259807
ISSN
0009-2797
Zeitschrift
CHEMICO-BIOLOGICAL INTERACTIONS
Schlüsselwörter
  • TCTP
  • AMG900
  • Molecular docking
  • Differentiation therapy
  • P53
  • Cancer
Artikelnummer
ARTN 109349
Datum der Veröffentlichung
2021
Status
Published
Titel
AMG900 as novel inhibitor of the translationally controlled tumor protein
Sub types
  • Article
Ausgabe der Zeitschrift
334

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.cbi.2020.109349
ISSN
0009-2797
Zeitschrift
Chemico-Biological Interactions
Sprache
en
Artikelnummer
109349
Paginierung
109349 - 109349
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.cbi.2020.109349
Datum der Datenerfassung
2021
Titel
AMG900 as novel inhibitor of the translationally controlled tumor protein
Ausgabe der Zeitschrift
334

Datenquelle: Crossref

Abstract
<h4>Introduction</h4>Cancer is one of the leading causes of death worldwide. Classical cytotoxic chemotherapy exerts high side effects and low tumor selectivity. Translationally controlled tumor protein (TCTP) is a target for differentiation therapy, a promising, new therapeutic approach, which is expected to be more selective and less toxic than cytotoxic chemotherapy. The aim of the present investigation was to identify novel TCTP inhibitors.<h4>Methods</h4>We performed in silico screening and molecular docking using a chemical library of more than 31,000 compounds to identify a novel inhibitor of TCTP. We tested AMG900 in vitro for binding to TCTP by microscale thermophoresis and co-immunoprecipitation. Additionally, we examined the effect of TCTP blockade on cell cycle progression by flow cytometry and Western blotting and cancer cell survival by resazurin assays in MCF-7, SK-OV3 and MOLT-4 cell lines.<h4>Results</h4>We identified AMG900 as new inhibitor of TCTP. AMG900 bound to the p53 binding site of TCTP with a free binding energy of -9.63 ± 0.01 kcal/mol. This compound decreased TCTP expression to 23.4 ± 1.59% and increased p53 expression to 194.29 ± 24.27%. Furthermore, AMG900 induced G0/G1 arrest as shown by flow cytometry and Western blot of relevant cell cycle proteins. AMG900 decreased CDK2, CDK4, CDK6, cyclin D1 and cyclin D3 expression, whereas p18, p21 and p27 expression increased. Moreover, AMG900 disturbed TCTP-p53 complexation as shown by co-immunoprecipitation and increased expression of free p53.<h4>Discussion</h4>AMG900 may serve as novel lead compound for the development of differentiation therapy approaches against cancer.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.cbi.2020.109349
eISSN
1872-7786
Externe Identifier
  • PubMed Identifier: 33259807
Open access
false
ISSN
0009-2797
Zeitschrift
Chemico-biological interactions
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasms
  • Phthalazines
  • Cell Cycle Proteins
  • G1 Phase
  • Apoptosis
  • Protein Biosynthesis
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Biomarkers, Tumor
  • Resting Phase, Cell Cycle
  • Tumor Protein, Translationally-Controlled 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Paginierung
109349
Datum der Veröffentlichung
2021
Status
Published
Datum der Datenerfassung
2020
Titel
AMG900 as novel inhibitor of the translationally controlled tumor protein.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
334

Datenquelle: Europe PubMed Central

Abstract
INTRODUCTION: Cancer is one of the leading causes of death worldwide. Classical cytotoxic chemotherapy exerts high side effects and low tumor selectivity. Translationally controlled tumor protein (TCTP) is a target for differentiation therapy, a promising, new therapeutic approach, which is expected to be more selective and less toxic than cytotoxic chemotherapy. The aim of the present investigation was to identify novel TCTP inhibitors. METHODS: We performed in silico screening and molecular docking using a chemical library of more than 31,000 compounds to identify a novel inhibitor of TCTP. We tested AMG900 in vitro for binding to TCTP by microscale thermophoresis and co-immunoprecipitation. Additionally, we examined the effect of TCTP blockade on cell cycle progression by flow cytometry and Western blotting and cancer cell survival by resazurin assays in MCF-7, SK-OV3 and MOLT-4 cell lines. RESULTS: We identified AMG900 as new inhibitor of TCTP. AMG900 bound to the p53 binding site of TCTP with a free binding energy of -9.63 ± 0.01 kcal/mol. This compound decreased TCTP expression to 23.4 ± 1.59% and increased p53 expression to 194.29 ± 24.27%. Furthermore, AMG900 induced G0/G1 arrest as shown by flow cytometry and Western blot of relevant cell cycle proteins. AMG900 decreased CDK2, CDK4, CDK6, cyclin D1 and cyclin D3 expression, whereas p18, p21 and p27 expression increased. Moreover, AMG900 disturbed TCTP-p53 complexation as shown by co-immunoprecipitation and increased expression of free p53. DISCUSSION: AMG900 may serve as novel lead compound for the development of differentiation therapy approaches against cancer.
Date of acceptance
2020
Autoren
  • Nicolas Fischer
  • Ean-Jeong Seo
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33259807
DOI
10.1016/j.cbi.2020.109349
eISSN
1872-7786
Zeitschrift
Chem Biol Interact
Schlüsselwörter
  • AMG900
  • Cancer
  • Differentiation therapy
  • Molecular docking
  • TCTP
  • p53
  • Apoptosis
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • G1 Phase
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Neoplasms
  • Phthalazines
  • Protein Biosynthesis
  • Resting Phase, Cell Cycle
  • Tumor Protein, Translationally-Controlled 1
Sprache
eng
Country
Ireland
Paginierung
109349
PII
S0009-2797(20)31806-8
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
AMG900 as novel inhibitor of the translationally controlled tumor protein.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
334

Datenquelle: PubMed

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