Discovery, design, and synthesis of indole-based EZH2 inhibitors

  • Bioorg Med Chem Lett. 2015 Sep 1;25(17):3644-9. doi: 10.1016/j.bmcl.2015.06.056.
Victor S Gehling  1 ,  Rishi G Vaswani  2 ,  Christopher G Nasveschuk  2 ,  Martin Duplessis  2 ,  Priyadarshini Iyer  2 ,  Srividya Balasubramanian  2 ,  Feng Zhao  2 ,  Andrew C Good  2 ,  Robert Campbell  2 ,  Christina Lee  2 ,  Les A Dakin  2 ,  Andrew S Cook  2 ,  Alexandre Gagnon  2 ,  Jean-Christophe Harmange  2 ,  James E Audia  2 ,  Richard T Cummings  2 ,  Emmanuel Normant  2 ,  Patrick Trojer  2 ,  Brian K Albrecht  2
Affiliations
  • 1. Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
  • 2. Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
PMID: 26189078 DOI: 10.1016/j.bmcl.2015.06.056
Abstract

The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.

Keywords
EZH2; Epigenetics; Histone methyltransferase; PRC2; Pyridone.