AMG900 as novel inhibitor of the translationally controlled tumor protein
| Autor: | Edmond Fleischer, Ean-Jeong Seo, Thomas Efferth, Anette Klinger, Nicolas Fischer |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Apoptosis Cell Cycle Proteins Toxicology Resting Phase Cell Cycle Flow cytometry 03 medical and health sciences 0302 clinical medicine Cyclin D1 Differentiation therapy Cell Line Tumor Neoplasms Translationally-controlled tumor protein Biomarkers Tumor medicine Humans Cyclin D3 medicine.diagnostic_test biology Chemistry G1 Phase Tumor Protein Translationally-Controlled 1 General Medicine Molecular Docking Simulation Blot 030104 developmental biology Protein Biosynthesis 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research biology.protein Phthalazines Cyclin-dependent kinase 6 |
| Zdroj: | Chemico-Biological Interactions. 334:109349 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2020.109349 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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