Literature DB >> 29456795

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

Biao Lu1, Xiaodong Shen1, Lei Zhang1, Dong Liu2, Caihua Zhang1, Jingsong Cao2, Ru Shen2, Jiayin Zhang2, Dan Wang1, Hong Wan1, Zhibin Xu1, Ming-Hsun Ho1, Minsheng Zhang2, Lianshan Zhang1, Feng He1, Weikang Tao1.   

Abstract

A novel series of benzofuran derived EZH2 inhibitors were discovered through a scaffold hopping approach based on the clinical compound of EPZ-6438. Further rational structure-activity relationship exploration and optimization led to the discovery of more potent EZH2 inhibitors with oral bioavailability in mice and rats. A lead compound EBI-2511 (compound 34) demonstrated excellent in vivo efficacy in Pfeiffer tumor Xenograft models in mouse and is under preclinical development for the treatment of cancers associated with EZH2 mutations.

Entities:  

Year:  2018        PMID： 29456795      PMCID： PMC5807876          DOI： 10.1021/acsmedchemlett.7b00437

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


  16 in total

1.  New lysine methyltransferase drug targets in cancer.

Authors:  Tobias Wagner; Manfred Jung
Journal:  Nat Biotechnol       Date:  2012-07-10       Impact factor: 54.908

2.  Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.

Authors:  Sarah K Knutson; Satoshi Kawano; Yukinori Minoshima; Natalie M Warholic; Kuan-Chun Huang; Yonghong Xiao; Tadashi Kadowaki; Mai Uesugi; Galina Kuznetsov; Namita Kumar; Tim J Wigle; Christine R Klaus; Christina J Allain; Alejandra Raimondi; Nigel J Waters; Jesse J Smith; Margaret Porter-Scott; Richard Chesworth; Mikel P Moyer; Robert A Copeland; Victoria M Richon; Toshimitsu Uenaka; Roy M Pollock; Kevin W Kuntz; Akira Yokoi; Heike Keilhack
Journal:  Mol Cancer Ther       Date:  2014-02-21       Impact factor: 6.261

3.  Stopping a chromatin enzyme.

Authors:  Jeffrey A Simon
Journal:  Nat Chem Biol       Date:  2012-11       Impact factor: 15.040

4.  EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.

Authors:  Michael T McCabe; Heidi M Ott; Gopinath Ganji; Susan Korenchuk; Christine Thompson; Glenn S Van Aller; Yan Liu; Alan P Graves; Anthony Della Pietra; Elsie Diaz; Louis V LaFrance; Mark Mellinger; Celine Duquenne; Xinrong Tian; Ryan G Kruger; Charles F McHugh; Martin Brandt; William H Miller; Dashyant Dhanak; Sharad K Verma; Peter J Tummino; Caretha L Creasy
Journal:  Nature       Date:  2012-10-10       Impact factor: 49.962

5.  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

6.  Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2.

Authors:  Christopher G Nasveschuk; Alexandre Gagnon; Shivani Garapaty-Rao; Srividya Balasubramanian; Robert Campbell; Christina Lee; Feng Zhao; Louise Bergeron; Richard Cummings; Patrick Trojer; James E Audia; Brian K Albrecht; Jean-Christophe P Harmange
Journal:  ACS Med Chem Lett       Date:  2014-01-14       Impact factor: 4.345

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.  The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat.

Authors:  Kevin W Kuntz; John E Campbell; Heike Keilhack; Roy M Pollock; Sarah K Knutson; Margaret Porter-Scott; Victoria M Richon; Chris J Sneeringer; Tim J Wigle; Christina J Allain; Christina R Majer; Mikel P Moyer; Robert A Copeland; Richard Chesworth
Journal:  J Med Chem       Date:  2016-01-27       Impact factor: 7.446

9.  Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas.

Authors:  Rishi G Vaswani; Victor S Gehling; Les A Dakin; Andrew S Cook; Christopher G Nasveschuk; Martin Duplessis; Priyadarshini Iyer; Srividya Balasubramanian; Feng Zhao; Andrew C Good; Robert Campbell; Christina Lee; Nico Cantone; Richard T Cummings; Emmanuel Normant; Steven F Bellon; Brian K Albrecht; Jean-Christophe Harmange; Patrick Trojer; James E Audia; Ying Zhang; Neil Justin; Shuyang Chen; Jon R Wilson; Steven J Gamblin
Journal:  J Med Chem       Date:  2016-10-28       Impact factor: 7.446

10.  Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.

Authors:  Ryan D Morin; Nathalie A Johnson; Tesa M Severson; Andrew J Mungall; Jianghong An; Rodrigo Goya; Jessica E Paul; Merrill Boyle; Bruce W Woolcock; Florian Kuchenbauer; Damian Yap; R Keith Humphries; Obi L Griffith; Sohrab Shah; Henry Zhu; Michelle Kimbara; Pavel Shashkin; Jean F Charlot; Marianna Tcherpakov; Richard Corbett; Angela Tam; Richard Varhol; Duane Smailus; Michelle Moksa; Yongjun Zhao; Allen Delaney; Hong Qian; Inanc Birol; Jacqueline Schein; Richard Moore; Robert Holt; Doug E Horsman; Joseph M Connors; Steven Jones; Samuel Aparicio; Martin Hirst; Randy D Gascoyne; Marco A Marra
Journal:  Nat Genet       Date:  2010-01-17       Impact factor: 38.330
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  6 in total

Review 1.  Lysine methyltransferase inhibitors: where we are now.

Authors:  Alessandra Feoli; Monica Viviano; Alessandra Cipriano; Ciro Milite; Sabrina Castellano; Gianluca Sbardella
Journal:  RSC Chem Biol       Date:  2021-12-13

Review 2.  Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity.

Authors:  Joviana Farhat; Lara Alzyoud; Mohammad Alwahsh; Basem Al-Omari
Journal:  Cancers (Basel)       Date:  2022-04-28       Impact factor: 6.575

3.  EZH2 inhibition: a promising strategy to prevent cancer immune editing.

Authors:  Ning Kang; Mark Eccleston; Pier-Luc Clermont; Maryam Latarani; David Kingsley Male; Yuzhuo Wang; Francesco Crea
Journal:  Epigenomics       Date:  2020-09-17       Impact factor: 4.778

4.  Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2.

Authors:  Qiaqia Li; Kilia Y Liu; Qipeng Liu; Guangyu Wang; Weihua Jiang; Qingshu Meng; Yang Yi; Yongyong Yang; Rui Wang; Sen Zhu; Chao Li; Longxiang Wu; Dongyu Zhao; Lin Yan; Lili Zhang; Jung-Sun Kim; Xiongbing Zu; Anthony J Kozielski; Wei Qian; Jenny C Chang; Akash Patnaik; Kaifu Chen; Qi Cao
Journal:  Mol Cancer Ther       Date:  2020-08-27       Impact factor: 6.261

Review 5.  Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds.

Authors:  Rossella Fioravanti; Giulia Stazi; Clemens Zwergel; Sergio Valente; Antonello Mai
Journal:  Chem Rec       Date:  2018-10-19       Impact factor: 6.771

Review 6.  EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications.

Authors:  Boheng Li; Wee-Joo Chng
Journal:  J Hematol Oncol       Date:  2019-11-21       Impact factor: 17.388
  6 in total

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