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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
  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:
Journal Article: 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.
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. doi:10.1074/jbc.m114.626861.
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. doi:10.1074/jbc.m114.626861. https://www.osti.gov/servlets/purl/1347984.
@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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