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Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.
Kim, Kyoung Soon; Zhang, Liping; Williams, David; Perez, Heidi L; Stang, Erik; Borzilleri, Robert M; Posy, Shana; Lei, Ming; Chaudhry, Charu; Emanuel, Stuart; Talbott, Randy.
Afiliación
  • Kim KS; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA. Electronic address: kyoung.kim@bms.com.
  • Zhang L; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Williams D; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Perez HL; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Stang E; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Borzilleri RM; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Posy S; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Lei M; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Chaudhry C; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Emanuel S; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
  • Talbott R; Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
Bioorg Med Chem Lett ; 24(21): 5022-9, 2014 Nov 01.
Article en En | MEDLINE | ID: mdl-25278234
Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Tetrahidroisoquinolinas / Proteínas Inhibidoras de la Apoptosis / Descubrimiento de Drogas / Melanoma / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Tetrahidroisoquinolinas / Proteínas Inhibidoras de la Apoptosis / Descubrimiento de Drogas / Melanoma / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido