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

  • ACS Med Chem Lett. 2015 Aug 27;7(2):134-8. doi: 10.1021/acsmedchemlett.5b00272.
Lorna H Mitchell  1 ,  P Ann Boriack-Sjodin  1 ,  Sherri Smith  1 ,  Michael Thomenius  1 ,  Nathalie Rioux  1 ,  Michael Munchhof  1 ,  James E Mills  1 ,  Christine Klaus  1 ,  Jennifer Totman  1 ,  Thomas V Riera  1 ,  Alejandra Raimondi  1 ,  Suzanne L Jacques  1 ,  Kip West  1 ,  Megan Foley  1 ,  Nigel J Waters  1 ,  Kevin W Kuntz  1 ,  Tim J Wigle  1 ,  Margaret Porter Scott  1 ,  Robert A Copeland  1 ,  Jesse J Smith  1 ,  Richard Chesworth  1
Affiliations
  • 1. Epizyme Inc. , Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States.
PMID: 26985287 DOI: 10.1021/acsmedchemlett.5b00272
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.

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