Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2

  • ACS Med Chem Lett. 2014 Jan 14;5(4):378-83. doi: 10.1021/ml400494b.
Christopher G Nasveschuk  1 ,  Alexandre Gagnon  1 ,  Shivani Garapaty-Rao  1 ,  Srividya Balasubramanian  1 ,  Robert Campbell  1 ,  Christina Lee  1 ,  Feng Zhao  1 ,  Louise Bergeron  1 ,  Richard Cummings  1 ,  Patrick Trojer  1 ,  James E Audia  1 ,  Brian K Albrecht  1 ,  Jean-Christophe P Harmange  1
Affiliations
  • 1. Constellation Pharmaceuticals , 215 1st Street, Suite 200, Cambridge, Massachusetts 02142, United States.
PMID: 24900844 DOI: 10.1021/ml400494b
Abstract

The identification and development of a novel series of small molecule Enhancer of Zeste Homologue 2 (EZH2) inhibitors is described. A concise and modular synthesis enabled the rapid development of structure-activity relationships, which led to the identification of 44 as a potent, SAM-competitive inhibitor of EZH2 that dose-dependently decreased global H3K27me3 in KARPAS-422 lymphoma cells.

Keywords
EZH2; KARPAS-422; PRC2; diphenylether; methyltransferase; tetramethylpiperidine.