Literature DB >> 24900844

Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2.

Christopher G Nasveschuk1, Alexandre Gagnon1, Shivani Garapaty-Rao1, Srividya Balasubramanian1, Robert Campbell1, Christina Lee1, Feng Zhao1, Louise Bergeron1, Richard Cummings1, Patrick Trojer1, James E Audia1, Brian K Albrecht1, Jean-Christophe P Harmange1.   

Abstract

The identification and development of a novel series of small molecule Enhancer of Zeste Homologue 2 (EZH2) inhibitors is described. A concise and modular synthesis enabled the rapid development of structure-activity relationships, which led to the identification of 44 as a potent, SAM-competitive inhibitor of EZH2 that dose-dependently decreased global H3K27me3 in KARPAS-422 lymphoma cells.

Entities:  

Keywords:  EZH2; KARPAS-422; PRC2; diphenylether; methyltransferase; tetramethylpiperidine

Year:  2014        PMID： 24900844      PMCID： PMC4027731          DOI： 10.1021/ml400494b

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  21 in total

1.  Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas.

Authors:  Christopher J Sneeringer; Margaret Porter Scott; Kevin W Kuntz; Sarah K Knutson; Roy M Pollock; Victoria M Richon; Robert A Copeland
Journal:  Proc Natl Acad Sci U S A       Date:  2010-11-15       Impact factor: 11.205

Review 2.  Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis.

Authors:  Ken A Brameld; Bernd Kuhn; Deborah C Reuter; Martin Stahl
Journal:  J Chem Inf Model       Date:  2008-01-10       Impact factor: 4.956

3.  The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations.

Authors:  Michael D Shultz
Journal:  Bioorg Med Chem Lett       Date:  2013-08-14       Impact factor: 2.823

4.  A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.

Authors:  Sarah K Knutson; Tim J Wigle; Natalie M Warholic; Christopher J Sneeringer; Christina J Allain; Christine R Klaus; Joelle D Sacks; Alejandra Raimondi; Christina R Majer; Jeffrey Song; Margaret Porter Scott; Lei Jin; Jesse J Smith; Edward J Olhava; Richard Chesworth; Mikel P Moyer; Victoria M Richon; Robert A Copeland; Heike Keilhack; Roy M Pollock; Kevin W Kuntz
Journal:  Nat Chem Biol       Date:  2012-09-30       Impact factor: 15.040

5.  The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states.

Authors:  Tim J Wigle; Sarah K Knutson; Lei Jin; Kevin W Kuntz; Roy M Pollock; Victoria M Richon; Robert A Copeland; Margaret Porter Scott
Journal:  FEBS Lett       Date:  2011-08-17       Impact factor: 4.124

6.  Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens.

Authors:  Elsie Diaz; Carl A Machutta; Stephanie Chen; Yong Jiang; Christopher Nixon; Glenn Hofmann; Danielle Key; Sharon Sweitzer; Mehul Patel; Zining Wu; Caretha L Creasy; Ryan G Kruger; Louis LaFrance; Sharad K Verma; Melissa B Pappalardi; Baochau Le; Glenn S Van Aller; Michael T McCabe; Peter J Tummino; Andrew J Pope; Sara H Thrall; Benjamin Schwartz; Martin Brandt
Journal:  J Biomol Screen       Date:  2012-08-17

7.  An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1.

Authors:  Kyle D Konze; Anqi Ma; Fengling Li; Dalia Barsyte-Lovejoy; Trevor Parton; Christopher J Macnevin; Feng Liu; Cen Gao; Xi-Ping Huang; Ekaterina Kuznetsova; Marie Rougie; Alice Jiang; Samantha G Pattenden; Jacqueline L Norris; Lindsey I James; Bryan L Roth; Peter J Brown; Stephen V Frye; Cheryl H Arrowsmith; Klaus M Hahn; Gang Greg Wang; Masoud Vedadi; Jian Jin
Journal:  ACS Chem Biol       Date:  2013-04-24       Impact factor: 5.100

8.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells.

Authors:  Celina G Kleer; Qi Cao; Sooryanarayana Varambally; Ronglai Shen; Ichiro Ota; Scott A Tomlins; Debashis Ghosh; Richard G A B Sewalt; Arie P Otte; Daniel F Hayes; Michael S Sabel; Donna Livant; Stephen J Weiss; Mark A Rubin; Arul M Chinnaiyan
Journal:  Proc Natl Acad Sci U S A       Date:  2003-09-19       Impact factor: 11.205

9.  Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth.

Authors:  Shivani Garapaty-Rao; Christopher Nasveschuk; Alexandre Gagnon; Eric Y Chan; Peter Sandy; Jennifer Busby; Srividya Balasubramanian; Robert Campbell; Feng Zhao; Louise Bergeron; James E Audia; Brian K Albrecht; Jean-Christophe Harmange; Richard Cummings; Patrick Trojer
Journal:  Chem Biol       Date:  2013-10-31

Review 10.  The Polycomb complex PRC2 and its mark in life.

Authors:  Raphaël Margueron; Danny Reinberg
Journal:  Nature       Date:  2011-01-20       Impact factor: 49.962
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  21 in total

Review 1.  Inhibitors of Protein Methyltransferases and Demethylases.

Authors:  H Ümit Kaniskan; Michael L Martini; Jian Jin
Journal:  Chem Rev       Date:  2017-03-24       Impact factor: 60.622

2.  Beyond PAINs: Chemotype Sensitivity of Protein Methyltransferases in Screens.

Authors:  Cen Gao; Brandon J Margolis; John M Strelow; Lewis R Vidler; Mary M Mader
Journal:  ACS Med Chem Lett       Date:  2015-11-19       Impact factor: 4.345

Review 3.  Structure, mechanism, and regulation of polycomb-repressive complex 2.

Authors:  Lindsay E Moritz; Raymond C Trievel
Journal:  J Biol Chem       Date:  2017-09-14       Impact factor: 5.157

4.  An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.

Authors:  Wei Qi; Kehao Zhao; Justin Gu; Ying Huang; Youzhen Wang; Hailong Zhang; Man Zhang; Jeff Zhang; Zhengtian Yu; Ling Li; Lin Teng; Shannon Chuai; Chao Zhang; Mengxi Zhao; HoMan Chan; Zijun Chen; Douglas Fang; Qi Fei; Leying Feng; Lijian Feng; Yuan Gao; Hui Ge; Xinjian Ge; Guobin Li; Andreas Lingel; Ying Lin; Yueqin Liu; Fangjun Luo; Minlong Shi; Long Wang; Zhaofu Wang; Yanyan Yu; Jue Zeng; Chenhui Zeng; Lijun Zhang; Qiong Zhang; Shaolian Zhou; Counde Oyang; Peter Atadja; En Li
Journal:  Nat Chem Biol       Date:  2017-01-30       Impact factor: 15.040

5.  Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment.

Authors:  Irene Marchesi; Luigi Bagella
Journal:  World J Clin Oncol       Date:  2016-04-10

6.  Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2.

Authors:  Marko Kalinić; Mire Zloh; Slavica Erić
Journal:  J Comput Aided Mol Des       Date:  2014-08-20       Impact factor: 3.686

7.  Structure-activity relationship studies of SETD8 inhibitors.

Authors:  Anqi Ma; Wenyu Yu; Yan Xiong; Kyle V Butler; Peter J Brown; Jian Jin
Journal:  Medchemcomm       Date:  2014-12       Impact factor: 3.597

Review 8.  A chemical probe toolbox for dissecting the cancer epigenome.

Authors:  Jake Shortt; Christopher J Ott; Ricky W Johnstone; James E Bradner
Journal:  Nat Rev Cancer       Date:  2017-02-23       Impact factor: 60.716

Review 9.  Inhibitors of protein methyltransferases as chemical tools.

Authors:  Minkui Luo
Journal:  Epigenomics       Date:  2015-12-08       Impact factor: 4.778

10.  Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin's Lymphoma.

Authors:  Biao Lu; Xiaodong Shen; Lei Zhang; Dong Liu; Caihua Zhang; Jingsong Cao; Ru Shen; Jiayin Zhang; Dan Wang; Hong Wan; Zhibin Xu; Ming-Hsun Ho; Minsheng Zhang; Lianshan Zhang; Feng He; Weikang Tao
Journal:  ACS Med Chem Lett       Date:  2018-01-29       Impact factor: 4.345
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