Literature DB >> 26985287

Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor.

Lorna H Mitchell1, P Ann Boriack-Sjodin1, Sherri Smith1, Michael Thomenius1, Nathalie Rioux1, Michael Munchhof1, James E Mills1, Christine Klaus1, Jennifer Totman1, Thomas V Riera1, Alejandra Raimondi1, Suzanne L Jacques1, Kip West1, Megan Foley1, Nigel J Waters1, Kevin W Kuntz1, Tim J Wigle1, Margaret Porter Scott1, Robert A Copeland1, Jesse J Smith1, Richard Chesworth1.   

Abstract

SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.

Entities:  

Keywords:  KMT; SMYD3; methyltransferase; oncology; oxindole; tool compound

Year:  2015        PMID： 26985287      PMCID： PMC4753551          DOI： 10.1021/acsmedchemlett.5b00272

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


  13 in total

1.  Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists.

Authors:  Robert A Copeland
Journal:  Methods Biochem Anal       Date:  2005

2.  Deregulated expression of selected histone methylases and demethylases in prostate carcinoma.

Authors:  Filipa Quintela Vieira; Pedro Costa-Pinheiro; João Ramalho-Carvalho; Andreia Pereira; Francisco Duarte Menezes; Luís Antunes; Isa Carneiro; Jorge Oliveira; Rui Henrique; Carmen Jerónimo
Journal:  Endocr Relat Cancer       Date:  2013-12-16       Impact factor: 5.678

3.  SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription.

Authors:  Cheng Liu; Chang Wang; Kun Wang; Li Liu; Qi Shen; Keqiang Yan; Xiaoqing Sun; Jie Chen; Jikai Liu; Hongbo Ren; Hainan Liu; Zhonghua Xu; Sanyuan Hu; Dawei Xu; Yidong Fan
Journal:  J Natl Cancer Inst       Date:  2013-10-30       Impact factor: 13.506

4.  Overexpression of SMYD3 and matrix metalloproteinase-9 are associated with poor prognosis of patients with gastric cancer.

Authors:  Yong Liu; Honggen Liu; Xuegang Luo; Jingyu Deng; Yuan Pan; Han Liang
Journal:  Tumour Biol       Date:  2015-01-28

5.  Overexpression of SMYD3 was associated with increased STAT3 activation in gastric cancer.

Authors:  Yong Liu; Jingyu Deng; Xuegang Luo; Yuan Pan; Li Zhang; Rupeng Zhang; Han Liang
Journal:  Med Oncol       Date:  2014-12-04       Impact factor: 3.064

6.  Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells.

Authors:  F Pittella Silva; R Hamamoto; M Kunizaki; M Tsuge; Y Nakamura; Y Furukawa
Journal:  Oncogene       Date:  2007-11-12       Impact factor: 9.867

7.  Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours.

Authors:  Marialuisa Sponziello; Cosimo Durante; Amelie Boichard; Mariavittoria Dima; Cinzia Puppin; Antonella Verrienti; Giulia Tamburrano; Giorgio Di Rocco; Adriano Redler; Ludovic Lacroix; Jean-Michel Bidart; Martin Schlumberger; Giuseppe Damante; Diego Russo; Sebastiano Filetti
Journal:  Mol Cell Endocrinol       Date:  2014-05-09       Impact factor: 4.102

8.  SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells.

Authors:  Ryuji Hamamoto; Yoichi Furukawa; Masashi Morita; Yuko Iimura; Fabio Pittella Silva; Meihua Li; Ryuichiro Yagyu; Yusuke Nakamura
Journal:  Nat Cell Biol       Date:  2004-07-04       Impact factor: 28.824

9.  SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3.

Authors:  Filipa Quintela Vieira; Pedro Costa-Pinheiro; Diogo Almeida-Rios; Inês Graça; Sara Monteiro-Reis; Susana Simões-Sousa; Isa Carneiro; Elsa Joana Sousa; Maria Inês Godinho; Fátima Baltazar; Rui Henrique; Carmen Jerónimo
Journal:  Oncotarget       Date:  2015-05-30

10.  SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.

Authors:  Pawel K Mazur; Nicolas Reynoird; Purvesh Khatri; Pascal W T C Jansen; Alex W Wilkinson; Shichong Liu; Olena Barbash; Glenn S Van Aller; Michael Huddleston; Dashyant Dhanak; Peter J Tummino; Ryan G Kruger; Benjamin A Garcia; Atul J Butte; Michiel Vermeulen; Julien Sage; Or Gozani
Journal:  Nature       Date:  2014-05-21       Impact factor: 49.962
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  29 in total

1.  Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

Authors:  Chuhui Huang; Si Si Liew; Grace R Lin; Anders Poulsen; Melgious J Y Ang; Brian C S Chia; Sin Yin Chew; Zekui P Kwek; John L K Wee; Esther H Ong; Priya Retna; Nithya Baburajendran; Rong Li; Weixuan Yu; Xiaoying Koh-Stenta; Anna Ngo; Sravanthy Manesh; Justina Fulwood; Zhiyuan Ke; Hwa Hwa Chung; Sugunavathi Sepramaniam; Xin Hui Chew; Nurul Dinie; May Ann Lee; Yun Shan Chew; Choon Bing Low; Vishal Pendharkar; Vithya Manoharan; Susmitha Vuddagiri; Kanda Sangthongpitag; Joma Joy; Alex Matter; Jeffrey Hill; Thomas H Keller; Klement Foo
Journal:  ACS Med Chem Lett       Date:  2019-05-23       Impact factor: 4.345

2.  Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1).

Authors:  H Ü Kaniskan; M S Eram; J Liu; D Smil; M L Martini; Y Shen; V Santhakumar; P J Brown; C Arrowsmith; M Vedadi; J Jin
Journal:  Medchemcomm       Date:  2016-07-13       Impact factor: 3.597

3.  Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

Authors:  Dai-Shi Su; Junya Qu; Mark Schulz; Chuck W Blackledge; Hongyi Yu; Jenny Zeng; Joelle Burgess; Alexander Reif; Melissa Stern; Raman Nagarajan; Melissa Baker Pappalardi; Kristen Wong; Alan P Graves; William Bonnette; Liping Wang; Patricia Elkins; Beth Knapp-Reed; Jeffrey D Carson; Charles McHugh; Helai Mohammad; Ryan Kruger; Juan Luengo; Dirk A Heerding; Caretha L Creasy
Journal:  ACS Med Chem Lett       Date:  2019-12-27       Impact factor: 4.345

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.  Novel insights into the oncogenic function of the SMYD3 lysine methyltransferase.

Authors:  Pawel K Mazur; Or Gozani; Julien Sage; Nicolas Reynoird
Journal:  Transl Cancer Res       Date:  2016-06       Impact factor: 1.241

6.  Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

Authors:  Yudao Shen; Magdalena M Szewczyk; Mohammad S Eram; David Smil; H Ümit Kaniskan; Renato Ferreira de Freitas; Guillermo Senisterra; Fengling Li; Matthieu Schapira; Peter J Brown; Cheryl H Arrowsmith; Dalia Barsyte-Lovejoy; Jing Liu; Masoud Vedadi; Jian Jin
Journal:  J Med Chem       Date:  2016-09-15       Impact factor: 7.446

Review 7.  Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.

Authors:  Kamakoti P Bhat; H Ümit Kaniskan; Jian Jin; Or Gozani
Journal:  Nat Rev Drug Discov       Date:  2021-01-19       Impact factor: 84.694

Review 8.  SET and MYND domain containing protein 3 in cancer.

Authors:  Lei Huang; A-Man Xu
Journal:  Am J Transl Res       Date:  2017-01-15       Impact factor: 4.060

9.  Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.

Authors:  Kyle V Butler; Anqi Ma; Wenyu Yu; Fengling Li; Wolfram Tempel; Nicolas Babault; Fabio Pittella-Silva; Jason Shao; Junyi Wang; Minkui Luo; Masoud Vedadi; Peter J Brown; Cheryl H Arrowsmith; Jian Jin
Journal:  J Med Chem       Date:  2016-11-02       Impact factor: 7.446

10.  A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases.

Authors:  Mohammad S Eram; Yudao Shen; Magdalena Szewczyk; Hong Wu; Guillermo Senisterra; Fengling Li; Kyle V Butler; H Ümit Kaniskan; Brandon A Speed; Carlo Dela Seña; Aiping Dong; Hong Zeng; Matthieu Schapira; Peter J Brown; Cheryl H Arrowsmith; Dalia Barsyte-Lovejoy; Jing Liu; Masoud Vedadi; Jian Jin
Journal:  ACS Chem Biol       Date:  2015-12-08       Impact factor: 5.100
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