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Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma
INTRODUCTION: Multiple myeloma (MM) is an extremely malignant and incurable hematological cancer. Increased expression of the c-Myc oncoprotein is closely associated with shorter overall survival of MM patients, implying that c-Myc is a potential therapeutic target. MAIN METHODS: We identified a pot...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532311/ https://www.ncbi.nlm.nih.gov/pubmed/33061303 http://dx.doi.org/10.2147/DDDT.S264077 |
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author | Yao, Ruosi Xie, Yu Sun, Xiaoyang Zhang, Menghui Zhou, Jian Liu, Linlin Gao, Jian Xu, Kailin |
author_facet | Yao, Ruosi Xie, Yu Sun, Xiaoyang Zhang, Menghui Zhou, Jian Liu, Linlin Gao, Jian Xu, Kailin |
author_sort | Yao, Ruosi |
collection | PubMed |
description | INTRODUCTION: Multiple myeloma (MM) is an extremely malignant and incurable hematological cancer. Increased expression of the c-Myc oncoprotein is closely associated with shorter overall survival of MM patients, implying that c-Myc is a potential therapeutic target. MAIN METHODS: We identified a potential c-Myc inhibitor 7594–0037 by structure-based virtual screening from the ChemDiv database. CCK8 assay and flow cytometry were used to detect MM cell viability, cell cycle and apoptosis. Q-PCR and Western blot were used to measure corresponding mRNA and protein expression levels. Protein stability assay measured the stability of c-Myc. RESULTS: Compound 7594–0037 exhibited stronger anti-proliferative activity against MM cells, and induced MM cell cycle G2 phase arrest and apoptosis. More importantly, compound 7594–0037 overcame myeloma resistance to bortezomib and exhibited a synergistic effect with bortezomib, resulting in increased MM cell death. The mechanism consists of compound 7594–0037 facilitating c-Myc protein degradation via decreasing the c-Myc S62 phosphorylation levels mediated by PIM1 kinase. Molecular dynamics simulation with the c-Myc/7594-0037 complex showed that compound 7594–0037 bound tightly to the N-terminus of c-Myc, and blocked the binding interaction of the two termini of c-Myc, which resulted in c-Myc entering into an unstable state. CONCLUSION: Overall, our study provides preliminary data for compound 7594–0037, which can be used as a novel c-Myc inhibitor and is a potential candidate therapeutic drug for multiple myeloma. |
format | Online Article Text |
id | pubmed-7532311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-75323112020-10-14 Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma Yao, Ruosi Xie, Yu Sun, Xiaoyang Zhang, Menghui Zhou, Jian Liu, Linlin Gao, Jian Xu, Kailin Drug Des Devel Ther Original Research INTRODUCTION: Multiple myeloma (MM) is an extremely malignant and incurable hematological cancer. Increased expression of the c-Myc oncoprotein is closely associated with shorter overall survival of MM patients, implying that c-Myc is a potential therapeutic target. MAIN METHODS: We identified a potential c-Myc inhibitor 7594–0037 by structure-based virtual screening from the ChemDiv database. CCK8 assay and flow cytometry were used to detect MM cell viability, cell cycle and apoptosis. Q-PCR and Western blot were used to measure corresponding mRNA and protein expression levels. Protein stability assay measured the stability of c-Myc. RESULTS: Compound 7594–0037 exhibited stronger anti-proliferative activity against MM cells, and induced MM cell cycle G2 phase arrest and apoptosis. More importantly, compound 7594–0037 overcame myeloma resistance to bortezomib and exhibited a synergistic effect with bortezomib, resulting in increased MM cell death. The mechanism consists of compound 7594–0037 facilitating c-Myc protein degradation via decreasing the c-Myc S62 phosphorylation levels mediated by PIM1 kinase. Molecular dynamics simulation with the c-Myc/7594-0037 complex showed that compound 7594–0037 bound tightly to the N-terminus of c-Myc, and blocked the binding interaction of the two termini of c-Myc, which resulted in c-Myc entering into an unstable state. CONCLUSION: Overall, our study provides preliminary data for compound 7594–0037, which can be used as a novel c-Myc inhibitor and is a potential candidate therapeutic drug for multiple myeloma. Dove 2020-09-28 /pmc/articles/PMC7532311/ /pubmed/33061303 http://dx.doi.org/10.2147/DDDT.S264077 Text en © 2020 Yao et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Yao, Ruosi Xie, Yu Sun, Xiaoyang Zhang, Menghui Zhou, Jian Liu, Linlin Gao, Jian Xu, Kailin Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title | Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title_full | Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title_fullStr | Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title_full_unstemmed | Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title_short | Identification of a Novel c-Myc Inhibitor 7594-0037 by Structure-Based Virtual Screening and Investigation of Its Anti-Cancer Effect on Multiple Myeloma |
title_sort | identification of a novel c-myc inhibitor 7594-0037 by structure-based virtual screening and investigation of its anti-cancer effect on multiple myeloma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532311/ https://www.ncbi.nlm.nih.gov/pubmed/33061303 http://dx.doi.org/10.2147/DDDT.S264077 |
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