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Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma
CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogen...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740082/ https://www.ncbi.nlm.nih.gov/pubmed/29269946 http://dx.doi.org/10.1038/s41598-017-18446-z |
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author | Drew, Allison E. Moradei, Oscar Jacques, Suzanne L. Rioux, Nathalie Boriack-Sjodin, Ann P. Allain, Christina Scott, Margaret Porter Jin, Lei Raimondi, Alejandra Handler, Jessica L. Ott, Heidi M. Kruger, Ryan G. McCabe, Michael T. Sneeringer, Christopher Riera, Thomas Shapiro, Gideon Waters, Nigel J. Mitchell, Lorna H. Duncan, Kenneth W. Moyer, Mikel P. Copeland, Robert A. Smith, Jesse Chesworth, Richard Ribich, Scott A. |
author_facet | Drew, Allison E. Moradei, Oscar Jacques, Suzanne L. Rioux, Nathalie Boriack-Sjodin, Ann P. Allain, Christina Scott, Margaret Porter Jin, Lei Raimondi, Alejandra Handler, Jessica L. Ott, Heidi M. Kruger, Ryan G. McCabe, Michael T. Sneeringer, Christopher Riera, Thomas Shapiro, Gideon Waters, Nigel J. Mitchell, Lorna H. Duncan, Kenneth W. Moyer, Mikel P. Copeland, Robert A. Smith, Jesse Chesworth, Richard Ribich, Scott A. |
author_sort | Drew, Allison E. |
collection | PubMed |
description | CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC(50) = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC(50) values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases. |
format | Online Article Text |
id | pubmed-5740082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57400822018-01-03 Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma Drew, Allison E. Moradei, Oscar Jacques, Suzanne L. Rioux, Nathalie Boriack-Sjodin, Ann P. Allain, Christina Scott, Margaret Porter Jin, Lei Raimondi, Alejandra Handler, Jessica L. Ott, Heidi M. Kruger, Ryan G. McCabe, Michael T. Sneeringer, Christopher Riera, Thomas Shapiro, Gideon Waters, Nigel J. Mitchell, Lorna H. Duncan, Kenneth W. Moyer, Mikel P. Copeland, Robert A. Smith, Jesse Chesworth, Richard Ribich, Scott A. Sci Rep Article CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC(50) = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC(50) values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases. Nature Publishing Group UK 2017-12-21 /pmc/articles/PMC5740082/ /pubmed/29269946 http://dx.doi.org/10.1038/s41598-017-18446-z Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Drew, Allison E. Moradei, Oscar Jacques, Suzanne L. Rioux, Nathalie Boriack-Sjodin, Ann P. Allain, Christina Scott, Margaret Porter Jin, Lei Raimondi, Alejandra Handler, Jessica L. Ott, Heidi M. Kruger, Ryan G. McCabe, Michael T. Sneeringer, Christopher Riera, Thomas Shapiro, Gideon Waters, Nigel J. Mitchell, Lorna H. Duncan, Kenneth W. Moyer, Mikel P. Copeland, Robert A. Smith, Jesse Chesworth, Richard Ribich, Scott A. Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title | Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title_full | Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title_fullStr | Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title_full_unstemmed | Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title_short | Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma |
title_sort | identification of a carm1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740082/ https://www.ncbi.nlm.nih.gov/pubmed/29269946 http://dx.doi.org/10.1038/s41598-017-18446-z |
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