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Selective targeting of MYC mRNA by stabilized antisense oligonucleotides
MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627489/ https://www.ncbi.nlm.nih.gov/pubmed/34650218 http://dx.doi.org/10.1038/s41388-021-02053-4 |
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author | Gill, Taylor Wang, Haichuan Bandaru, Raj Lawlor, Matthew Lu, Chenyue Nieman, Linda T. Tao, Junyan Zhang, Yixian Anderson, Daniel G. Ting, David T. Chen, Xin Bradner, James E. Ott, Christopher J. |
author_facet | Gill, Taylor Wang, Haichuan Bandaru, Raj Lawlor, Matthew Lu, Chenyue Nieman, Linda T. Tao, Junyan Zhang, Yixian Anderson, Daniel G. Ting, David T. Chen, Xin Bradner, James E. Ott, Christopher J. |
author_sort | Gill, Taylor |
collection | PubMed |
description | MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5’- and 3’-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5’ Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors. |
format | Online Article Text |
id | pubmed-8627489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-86274892022-04-14 Selective targeting of MYC mRNA by stabilized antisense oligonucleotides Gill, Taylor Wang, Haichuan Bandaru, Raj Lawlor, Matthew Lu, Chenyue Nieman, Linda T. Tao, Junyan Zhang, Yixian Anderson, Daniel G. Ting, David T. Chen, Xin Bradner, James E. Ott, Christopher J. Oncogene Article MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5’- and 3’-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5’ Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors. 2021-10-14 2021-11 /pmc/articles/PMC8627489/ /pubmed/34650218 http://dx.doi.org/10.1038/s41388-021-02053-4 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: <uri xlink:href="https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms"> |
spellingShingle | Article Gill, Taylor Wang, Haichuan Bandaru, Raj Lawlor, Matthew Lu, Chenyue Nieman, Linda T. Tao, Junyan Zhang, Yixian Anderson, Daniel G. Ting, David T. Chen, Xin Bradner, James E. Ott, Christopher J. Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title | Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title_full | Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title_fullStr | Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title_full_unstemmed | Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title_short | Selective targeting of MYC mRNA by stabilized antisense oligonucleotides |
title_sort | selective targeting of myc mrna by stabilized antisense oligonucleotides |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627489/ https://www.ncbi.nlm.nih.gov/pubmed/34650218 http://dx.doi.org/10.1038/s41388-021-02053-4 |
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