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

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• 作者：Lorna H. Mitchell ; P. Ann Boriack-Sjodin ; Sherri Smith ; Michael Thomenius ; Nathalie Rioux ; Michael Munchhof ; James E. Mills ; Christine Klaus ; Jennifer Totman ; Thomas V. Riera ; Alejandra Raimondi ; Suzanne L. Jacques ; Kip West ; Megan Foley ; Nigel J. Waters ; Kevin W. Kuntz ; Tim J. Wigle ; Margaret Porter Scott ; Robert A. Copeland ; Jesse J. Smith ; Richard Chesworth
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：7
• 期：2
• 页码：134-138
• 全文大小：315K
• ISSN：1948-5875

文摘

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.