2. Academic Validation
  3. Discovery, design, and synthesis of indole-based EZH2 inhibitors

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

Affiliations

  • 1 Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA. Electronic address: victor.gehling@constellationpharma.com.
  • 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.

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