Literature DB >> 32071679

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

Dai-Shi Su1, Junya Qu1, Mark Schulz1, Chuck W Blackledge1, Hongyi Yu1, Jenny Zeng1, Joelle Burgess1, Alexander Reif1, Melissa Stern1, Raman Nagarajan1, Melissa Baker Pappalardi1, Kristen Wong1, Alan P Graves1, William Bonnette1, Liping Wang1, Patricia Elkins1, Beth Knapp-Reed1, Jeffrey D Carson1, Charles McHugh1, Helai Mohammad1, Ryan Kruger1, Juan Luengo1, Dirk A Heerding1, Caretha L Creasy1.   

Abstract

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.
Copyright © 2019 American Chemical Society.

Entities:  

Year:  2019        PMID： 32071679      PMCID： PMC7025381          DOI： 10.1021/acsmedchemlett.9b00493

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


  15 in total

Review 1.  Beyond histones - the expanding roles of protein lysine methylation.

Authors:  Zhouran Wu; Justin Connolly; Kyle K Biggar
Journal:  FEBS J       Date:  2017-05-02       Impact factor: 5.542

2.  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

3.  Elevated Levels of SET and MYND Domain-Containing Protein 3 Are Correlated with Overexpression of Transforming Growth Factor-β1 in Gastric Cancer.

Authors:  Honggen Liu; Yong Liu; Fanming Kong; Wen Xin; Xiaojiang Li; Han Liang; Yingjie Jia
Journal:  J Am Coll Surg       Date:  2015-03-04       Impact factor: 6.113

Review 4.  RAS oncogenes: weaving a tumorigenic web.

Authors:  Yuliya Pylayeva-Gupta; Elda Grabocka; Dafna Bar-Sagi
Journal:  Nat Rev Cancer       Date:  2011-10-13       Impact factor: 60.716

5.  Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets.

Authors:  Glenn S Van Aller; Alan P Graves; Patricia A Elkins; William G Bonnette; Patrick J McDevitt; Francesca Zappacosta; Roland S Annan; Tony W Dean; Dai-Shi Su; Christopher L Carpenter; Helai P Mohammad; Ryan G Kruger
Journal:  Structure       Date:  2016-04-07       Impact factor: 5.006

6.  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

7.  Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation.

Authors:  Glenn S Van Aller; Nicolas Reynoird; Olena Barbash; Michael Huddleston; Shichong Liu; Anne-Flore Zmoos; Patrick McDevitt; Robert Sinnamon; BaoChau Le; Gloria Mas; Roland Annan; Julien Sage; Benjamin A Garcia; Peter J Tummino; Or Gozani; Ryan G Kruger
Journal:  Epigenetics       Date:  2012-04-01       Impact factor: 4.528

8.  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

9.  Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.

Authors:  Lanxin Liu; Sarah Kimball; Hui Liu; Andreana Holowatyj; Zeng-Quan Yang
Journal:  Oncotarget       Date:  2015-02-10

10.  Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation.

Authors:  Michael J Thomenius; Jennifer Totman; Darren Harvey; Lorna H Mitchell; Thomas V Riera; Kat Cosmopoulos; Alexandra R Grassian; Christine Klaus; Megan Foley; Elizabeth A Admirand; Haris Jahic; Christina Majer; Tim Wigle; Suzanne L Jacques; Jodi Gureasko; Dorothy Brach; Trupti Lingaraj; Kip West; Sherri Smith; Nathalie Rioux; Nigel J Waters; Cuyue Tang; Alejandra Raimondi; Michael Munchhof; James E Mills; Scott Ribich; Margaret Porter Scott; Kevin W Kuntz; William P Janzen; Mikel Moyer; Jesse J Smith; Richard Chesworth; Robert A Copeland; P Ann Boriack-Sjodin
Journal:  PLoS One       Date:  2018-06-01       Impact factor: 3.240
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  3 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

2.  Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase.

Authors:  Vladimir O Talibov; Edoardo Fabini; Edward A FitzGerald; Daniele Tedesco; Daniela Cederfeldt; Martin J Talu; Moira M Rachman; Filip Mihalic; Elisabetta Manoni; Marina Naldi; Paola Sanese; Giovanna Forte; Martina Lepore Signorile; Xavier Barril; Cristiano Simone; Manuela Bartolini; Doreen Dobritzsch; Alberto Del Rio; U Helena Danielson
Journal:  Chembiochem       Date:  2021-02-11       Impact factor: 3.164

3.  Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors.

Authors:  Shunzhou Wan; Agastya P Bhati; David W Wright; Ian D Wall; Alan P Graves; Darren Green; Peter V Coveney
Journal:  J Chem Inf Model       Date:  2022-05-04       Impact factor: 6.162
  3 in total

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