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Title: LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2

Abstract

SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor typesmore » that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. As a result, these findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [4];  [2] more »;  [1];  [3];  [2];  [1];  [2] « less
+ Show Author Affiliations
  1. Eli Lily and Co., Indianapolis, IN (United States)
  2. Univ. of Toronto, Toronto, ON (Canada)
  3. Univ. of Pennsylvania, Philadelphia, PA (United States)
  4. Univ. of Toronto, Toronto, ON (Canada); Univ. of Toronto and Princess Margaret Cancer Centre, Toronto, ON (Canada)
Publication Date:
Research Org.:
UChicago, LLC., Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1347984
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 22; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; SMYD2; cancer biology; chemical probe; crystal structure; enzyme inhibitor; epigenetics; methyltransferase; protein methylation

Citation Formats

Nguyen, Hannah, Allali-Hassani, Abdellah, Antonysamy, Stephen, Chang, Shawn, Chen, Lisa Hong, Curtis, Carmen, Emtage, Spencer, Fan, Li, Gheyi, Tarun, Li, Fengling, Liu, Shichong, Martin, Joseph R., Mendel, David, Olsen, Jonathan B., Pelletier, Laura, Shatseva, Tatiana, Wu, Song, Zhang, Feiyu Fred, Arrowsmith, Cheryl H., Brown, Peter J., Campbell, Robert M., Garcia, Benjamin A., Barsyte-Lovejoy, Dalia, Mader, Mary, and Vedadi, Masoud. LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. United States: N. p., 2015. Web. doi:10.1074/jbc.m114.626861.
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Nguyen, Hannah, Allali-Hassani, Abdellah, Antonysamy, Stephen, Chang, Shawn, Chen, Lisa Hong, Curtis, Carmen, Emtage, Spencer, Fan, Li, Gheyi, Tarun, Li, Fengling, Liu, Shichong, Martin, Joseph R., Mendel, David, Olsen, Jonathan B., Pelletier, Laura, Shatseva, Tatiana, Wu, Song, Zhang, Feiyu Fred, Arrowsmith, Cheryl H., Brown, Peter J., Campbell, Robert M., Garcia, Benjamin A., Barsyte-Lovejoy, Dalia, Mader, Mary, & Vedadi, Masoud. LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. United States. https://doi.org/10.1074/jbc.m114.626861
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Nguyen, Hannah, Allali-Hassani, Abdellah, Antonysamy, Stephen, Chang, Shawn, Chen, Lisa Hong, Curtis, Carmen, Emtage, Spencer, Fan, Li, Gheyi, Tarun, Li, Fengling, Liu, Shichong, Martin, Joseph R., Mendel, David, Olsen, Jonathan B., Pelletier, Laura, Shatseva, Tatiana, Wu, Song, Zhang, Feiyu Fred, Arrowsmith, Cheryl H., Brown, Peter J., Campbell, Robert M., Garcia, Benjamin A., Barsyte-Lovejoy, Dalia, Mader, Mary, and Vedadi, Masoud. Mon . "LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2". United States. https://doi.org/10.1074/jbc.m114.626861. https://www.osti.gov/servlets/purl/1347984.
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@article{osti_1347984,
title = {LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2},
author = {Nguyen, Hannah and Allali-Hassani, Abdellah and Antonysamy, Stephen and Chang, Shawn and Chen, Lisa Hong and Curtis, Carmen and Emtage, Spencer and Fan, Li and Gheyi, Tarun and Li, Fengling and Liu, Shichong and Martin, Joseph R. and Mendel, David and Olsen, Jonathan B. and Pelletier, Laura and Shatseva, Tatiana and Wu, Song and Zhang, Feiyu Fred and Arrowsmith, Cheryl H. and Brown, Peter J. and Campbell, Robert M. and Garcia, Benjamin A. and Barsyte-Lovejoy, Dalia and Mader, Mary and Vedadi, Masoud},
abstractNote = {SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. As a result, these findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.},
doi = {10.1074/jbc.m114.626861},
journal = {Journal of Biological Chemistry},
number = 22,
volume = 290,
place = {United States},
year = {Mon Mar 30 00:00:00 EDT 2015},
month = {Mon Mar 30 00:00:00 EDT 2015}
}
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https://doi.org/10.1074/jbc.m114.626861
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Structural Insights into Estrogen Receptor α Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation
journal, October 2014

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  • Journal of Molecular Biology, Vol. 426, Issue 20
  • DOI: 10.1016/j.jmb.2014.02.019

SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor
journal, April 2014

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Structural Basis of Substrate Methylation and Inhibition of SMYD2
journal, September 2011

Biochemical Characterization of Human SET and MYND Domain-Containing Protein 2 Methyltransferase
journal, July 2011

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  • Biochemistry, Vol. 50, Issue 29
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Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions
journal, February 2008

Chromatin proteins and modifications as drug targets
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SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer
journal, May 2014

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  • Nature, Vol. 510, Issue 7504
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The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
journal, September 2007

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Epigenetic protein families: a new frontier for drug discovery
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Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
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SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos
journal, February 2006

  • Tan, X.; Rotllant, J.; Li, H.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 8
  • DOI: 10.1073/pnas.0509503103

Regulation of estrogen receptor   by histone methyltransferase SMYD2-mediated protein methylation
journal, October 2013

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Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma
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  • Komatsu, Shuhei; Imoto, Issei; Tsuda, Hitoshi
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  • DOI: 10.1093/carcin/bgp116

Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization
journal, January 2012

Identification of Smyd4 as a Potential Tumor Suppressor Gene Involved in Breast Cancer Development
journal, April 2009

Cancer epigenetics drug discovery and development: the challenge of hitting the mark
journal, January 2014

  • Campbell, Robert M.; Tummino, Peter J.
  • Journal of Clinical Investigation, Vol. 124, Issue 1
  • DOI: 10.1172/jci71605

Crystal Structures of Histone and p53 Methyltransferase SmyD2 Reveal a Conformational Flexibility of the Autoinhibitory C-Terminal Domain
journal, June 2011

RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation
journal, June 2012

  • Cho, Hyun-Soo; Hayami, Shinya; Toyokawa, Gouji
  • Neoplasia, Vol. 14, Issue 6
  • DOI: 10.1593/neo.12656

Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation
journal, April 2012

  • Van Aller, Glenn S.; Reynoird, Nicolas; Barbash, Olena
  • Epigenetics, Vol. 7, Issue 4
  • DOI: 10.4161/epi.19506
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