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Title: SAH derived potent and selective EZH2 inhibitors

Abstract

A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50’s against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405013
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 25; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kung, Pei-Pei, Huang, Buwen, Zehnder, Luke, Tatlock, John, Bingham, Patrick, Krivacic, Cody, Gajiwala, Ketan, Diehl, Wade, Yu, Xiu, and Maegley, Karen A. SAH derived potent and selective EZH2 inhibitors. United States: N. p., 2015. Web. doi:10.1016/j.bmcl.2015.02.017.
Kung, Pei-Pei, Huang, Buwen, Zehnder, Luke, Tatlock, John, Bingham, Patrick, Krivacic, Cody, Gajiwala, Ketan, Diehl, Wade, Yu, Xiu, & Maegley, Karen A. SAH derived potent and selective EZH2 inhibitors. United States. doi:10.1016/j.bmcl.2015.02.017.
Kung, Pei-Pei, Huang, Buwen, Zehnder, Luke, Tatlock, John, Bingham, Patrick, Krivacic, Cody, Gajiwala, Ketan, Diehl, Wade, Yu, Xiu, and Maegley, Karen A. Wed . "SAH derived potent and selective EZH2 inhibitors". United States. doi:10.1016/j.bmcl.2015.02.017.
@article{osti_1405013,
title = {SAH derived potent and selective EZH2 inhibitors},
author = {Kung, Pei-Pei and Huang, Buwen and Zehnder, Luke and Tatlock, John and Bingham, Patrick and Krivacic, Cody and Gajiwala, Ketan and Diehl, Wade and Yu, Xiu and Maegley, Karen A.},
abstractNote = {A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50’s against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.},
doi = {10.1016/j.bmcl.2015.02.017},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 7,
volume = 25,
place = {United States},
year = {Wed Apr 01 00:00:00 EDT 2015},
month = {Wed Apr 01 00:00:00 EDT 2015}
}