Open AccessNovel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor
Author(s) -
Lorna H. Mitchell,
P. Ann BoriackSjodin,
Sherri Smith,
Michael J. Thomenius,
Nathalie Rioux,
Michael J. Munchhof,
James E. Mills,
Christine Klaus,
Jennifer Totman,
Thomas V. Riera,
Alejandra Raimondi,
Suzanne L. Jacques,
Kip A. West,
Megan Foley,
Nigel J. Waters,
Kevin W. Kuntz,
Tim J. Wigle,
Margaret Porter Scott,
Robert A. Copeland,
J. Joshua Smith,
Richard Chesworth
Publication year - 2015
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.5b00272
Subject(s) - sulfonamide , oxindole , pharmacology , sulfamide , in vivo , bioavailability , potency , chemistry , small molecule , methyltransferase , histone methyltransferase , drug discovery , in vitro , computational biology , medicine , biochemistry , biology , histone , stereochemistry , methylation , microbiology and biotechnology , organic chemistry , gene , catalysis
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.