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Discovery, design, and synthesis of indole-based EZH2 inhibitors.
Gehling, Victor S; Vaswani, Rishi G; Nasveschuk, Christopher G; Duplessis, Martin; Iyer, Priyadarshini; Balasubramanian, Srividya; Zhao, Feng; Good, Andrew C; Campbell, Robert; Lee, Christina; Dakin, Les A; Cook, Andrew S; Gagnon, Alexandre; Harmange, Jean-Christophe; Audia, James E; Cummings, Richard T; Normant, Emmanuel; Trojer, Patrick; Albrecht, Brian K.
Afiliação
  • Gehling VS; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA. Electronic address: victor.gehling@constellationpharma.com.
  • Vaswani RG; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Nasveschuk CG; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Duplessis M; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Iyer P; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Balasubramanian S; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Zhao F; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Good AC; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Campbell R; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Lee C; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Dakin LA; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Cook AS; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Gagnon A; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Harmange JC; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Audia JE; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Cummings RT; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Normant E; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Trojer P; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
  • Albrecht BK; Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett ; 25(17): 3644-9, 2015 Sep 01.
Article em En | MEDLINE | ID: mdl-26189078
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Complexo Repressor Polycomb 2 / Indóis / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Complexo Repressor Polycomb 2 / Indóis / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article