Literature DB >> 26985292

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.

Kenneth W Duncan1, Nathalie Rioux1, P Ann Boriack-Sjodin1, Michael J Munchhof1, Lawrence A Reiter1, Christina R Majer1, Lei Jin1, L Danielle Johnston1, Elayne Chan-Penebre1, Kristy G Kuplast1, Margaret Porter Scott1, Roy M Pollock1, Nigel J Waters1, Jesse J Smith1, Mikel P Moyer1, Robert A Copeland1, Richard Chesworth1.   

Abstract

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).

Entities:  

Keywords:  Methyltransferase; PRMT5; property based optimization; structure guided design

Year:  2015        PMID： 26985292      PMCID： PMC4753547          DOI： 10.1021/acsmedchemlett.5b00380

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


  16 in total

1.  Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.

Authors:  Sharmistha Pal; Sheethal N Vishwanath; Hediye Erdjument-Bromage; Paul Tempst; Saïd Sif
Journal:  Mol Cell Biol       Date:  2004-11       Impact factor: 4.272

Review 2.  Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety.

Authors:  Nicholas A Meanwell
Journal:  Chem Res Toxicol       Date:  2011-07-26       Impact factor: 3.739

3.  Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.

Authors:  Nathalie Rioux; Kenneth W Duncan; Ronald J Lantz; Xiusheng Miao; Elayne Chan-Penebre; Mikel P Moyer; Michael J Munchhof; Robert A Copeland; Richard Chesworth; Nigel J Waters
Journal:  Xenobiotica       Date:  2016       Impact factor: 1.908

4.  Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4.

Authors:  Matthew A Powers; Marta M Fay; Rachel E Factor; Alana L Welm; Katharine S Ullman
Journal:  Cancer Res       Date:  2011-06-23       Impact factor: 12.701

Review 5.  Versatility of PRMT5-induced methylation in growth control and development.

Authors:  Vrajesh Karkhanis; Yu-Jie Hu; Robert A Baiocchi; Anthony N Imbalzano; Saïd Sif
Journal:  Trends Biochem Sci       Date:  2011-10-03       Impact factor: 13.807

6.  Crystal structure of the human PRMT5:MEP50 complex.

Authors:  Stephen Antonysamy; Zahid Bonday; Robert M Campbell; Brandon Doyle; Zhanna Druzina; Tarun Gheyi; Bomie Han; Louis N Jungheim; Yuewei Qian; Charles Rauch; Marijane Russell; J Michael Sauder; Stephen R Wasserman; Kenneth Weichert; Francis S Willard; Aiping Zhang; Spencer Emtage
Journal:  Proc Natl Acad Sci U S A       Date:  2012-10-15       Impact factor: 11.205

7.  Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells.

Authors:  Li Wang; Sharmistha Pal; Saïd Sif
Journal:  Mol Cell Biol       Date:  2008-08-11       Impact factor: 4.272

8.  Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma.

Authors:  Sharmistha Pal; Robert A Baiocchi; John C Byrd; Michael R Grever; Samson T Jacob; Saïd Sif
Journal:  EMBO J       Date:  2007-07-12       Impact factor: 11.598

9.  Arginine methylation controls growth regulation by E2F-1.

Authors:  Er-Chieh Cho; Shunsheng Zheng; Shonagh Munro; Geng Liu; Simon M Carr; Jutta Moehlenbrink; Yi-Chien Lu; Lindsay Stimson; Omar Khan; Rebecca Konietzny; Joanna McGouran; Amanda S Coutts; Benedikt Kessler; David J Kerr; Nicholas B La Thangue
Journal:  EMBO J       Date:  2012-02-10       Impact factor: 11.598

10.  Selective inhibitors of protein methyltransferases.

Authors:  H Ümit Kaniskan; Kyle D Konze; Jian Jin
Journal:  J Med Chem       Date:  2014-12-02       Impact factor: 7.446
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  44 in total

Review 1.  Small Molecule Inhibitors of Protein Arginine Methyltransferases.

Authors:  Hao Hu; Kun Qian; Meng-Chiao Ho; Y George Zheng
Journal:  Expert Opin Investig Drugs       Date:  2016-02-16       Impact factor: 6.206

2.  PRMT1 Plays a Critical Role in Th17 Differentiation by Regulating Reciprocal Recruitment of STAT3 and STAT5.

Authors:  Subha Sen; Zhiheng He; Shubhamoy Ghosh; Kenneth J Dery; Lu Yang; Jing Zhang; Zuoming Sun
Journal:  J Immunol       Date:  2018-05-23       Impact factor: 5.422

Review 3.  Protein arginine methylation: from enigmatic functions to therapeutic targeting.

Authors:  Qin Wu; Matthieu Schapira; Cheryl H Arrowsmith; Dalia Barsyte-Lovejoy
Journal:  Nat Rev Drug Discov       Date:  2021-03-19       Impact factor: 84.694

Review 4.  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

5.  Islet-specific Prmt5 excision leads to reduced insulin expression and glucose intolerance in mice.

Authors:  Jian Ma; Xin He; Yan Cao; Kienan O'Dwyer; Katherine M Szigety; Yuan Wu; Buddha Gurung; Zijie Feng; Bryson W Katona; Xianxin Hua
Journal:  J Endocrinol       Date:  2020-01-01       Impact factor: 4.286

6.  Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5).

Authors:  Rachel L Palte; Sebastian E Schneider; Michael D Altman; Robert P Hayes; Shuhei Kawamura; Brian M Lacey; My Sam Mansueto; Michael Reutershan; Phieng Siliphaivanh; Christopher Sondey; Haiyan Xu; Zangwei Xu; Yingchun Ye; Michelle R Machacek
Journal:  ACS Med Chem Lett       Date:  2020-08-07       Impact factor: 4.345

7.  Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

Authors:  Jia Yi Fong; Luca Pignata; Pierre-Alexis Goy; Kimihito Cojin Kawabata; Stanley Chun-Wei Lee; Cheryl M Koh; Daniele Musiani; Enrico Massignani; Andriana G Kotini; Alex Penson; Cheng Mun Wun; Yudao Shen; Megan Schwarz; Diana Hp Low; Alexander Rialdi; Michelle Ki; Heike Wollmann; Slim Mzoughi; Florence Gay; Christine Thompson; Timothy Hart; Olena Barbash; Genna M Luciani; Magdalena M Szewczyk; Bas J Wouters; Ruud Delwel; Eirini P Papapetrou; Dalia Barsyte-Lovejoy; Cheryl H Arrowsmith; Mark D Minden; Jian Jin; Ari Melnick; Tiziana Bonaldi; Omar Abdel-Wahab; Ernesto Guccione
Journal:  Cancer Cell       Date:  2019-08-12       Impact factor: 31.743

8.  LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.

Authors:  Zahid Q Bonday; Guillermo S Cortez; Michael J Grogan; Stephen Antonysamy; Ken Weichert; Wayne P Bocchinfuso; Fengling Li; Steven Kennedy; Binghui Li; Mary M Mader; Cheryl H Arrowsmith; Peter J Brown; Mohammad S Eram; Magdalena M Szewczyk; Dalia Barsyte-Lovejoy; Masoud Vedadi; Ernesto Guccione; Robert M Campbell
Journal:  ACS Med Chem Lett       Date:  2018-04-23       Impact factor: 4.345

Review 9.  Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities.

Authors:  Maxime Blijlevens; Jing Li; Victor W van Beusechem
Journal:  Int J Mol Sci       Date:  2021-05-12       Impact factor: 5.923

10.  PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival.

Authors:  Xiaoqing Lu; Tharu M Fernando; Chen Lossos; Nevin Yusufova; Fan Liu; Lorena Fontán; Matthew Durant; Huimin Geng; Jacob Melnick; Yuan Luo; Francisco Vega; Vincent Moy; Giorgio Inghirami; Stephen Nimer; Ari M Melnick; Izidore S Lossos
Journal:  Blood       Date:  2018-08-06       Impact factor: 22.113
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