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Identification of potent, selective KDM5 inhibitors.
Gehling, Victor S; Bellon, Steven F; Harmange, Jean-Christophe; LeBlanc, Yves; Poy, Florence; Odate, Shobu; Buker, Shane; Lan, Fei; Arora, Shilpi; Williamson, Kaylyn E; Sandy, Peter; Cummings, Richard T; Bailey, Christopher M; Bergeron, Louise; Mao, Weifeng; Gustafson, Amy; Liu, Yichin; VanderPorten, Erica; Audia, James E; Trojer, Patrick; Albrecht, Brian K.
Afiliación
  • Gehling VS; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States. Electronic address: victor.gehling@constellationpharma.com.
  • Bellon SF; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Harmange JC; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • LeBlanc Y; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Poy F; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Odate S; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Buker S; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Lan F; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Arora S; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Williamson KE; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Sandy P; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Cummings RT; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Bailey CM; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Bergeron L; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Mao W; WuXi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • Gustafson A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • Liu Y; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • VanderPorten E; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • Audia JE; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Trojer P; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • Albrecht BK; Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
Bioorg Med Chem Lett ; 26(17): 4350-4, 2016 09 01.
Article en En | MEDLINE | ID: mdl-27476424
ABSTRACT
This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Proteína 2 de Unión a Retinoblastoma Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Proteína 2 de Unión a Retinoblastoma Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article