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Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.
Liu, Gang; Abraham, Sunny; Liu, Xing; Xu, Shimin; Rooks, Allison M; Nepomuceno, Ron; Dao, Alan; Brigham, Daniel; Gitnick, Dana; Insko, Darren E; Gardner, Michael F; Zarrinkar, Patrick P; Christopher, Ron; Belli, Barbara; Armstrong, Robert C; Holladay, Mark W.
Afiliación
  • Liu G; Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA. Electronic address: liugx1@gmail.com.
  • Abraham S; Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Liu X; Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Xu S; Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Rooks AM; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Nepomuceno R; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Dao A; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Brigham D; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Gitnick D; DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Insko DE; DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Gardner MF; DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Zarrinkar PP; Technology Development, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Christopher R; DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Belli B; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Armstrong RC; Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
  • Holladay MW; Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
Bioorg Med Chem Lett ; 25(17): 3436-41, 2015 Sep 01.
Article en En | MEDLINE | ID: mdl-26208887
ABSTRACT
Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tirosina Quinasa 3 Similar a fms / Aminopiridinas / Antineoplásicos Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article
Texto completo
Imprimir
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tirosina Quinasa 3 Similar a fms / Aminopiridinas / Antineoplásicos Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article