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Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.
Hill, Matthew D; Fang, Haiquan; Tokarski, John; Fanslau, Carolynn; Haarhoff, Zuzana; Huang, Christine; Kramer, Melissa; Menard, Krista; Monereau, Laura; Morrison, John; Ranasinghe, Asoka; Shields, Eric E; Tye, Ching Kim; Westhouse, Richard; Everlof, Gerry; Sheriff, Steven; Yan, Chunhong; Marsilio, Frank; Zhang, Lisa; Zvyaga, Tatyana; Lee, Francis; Gavai, Ashvinikumar V; Degnan, Andrew P.
Afiliación
  • Hill MD; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA. Electronic address: matthew.hill@bms.com.
  • Fang H; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Tokarski J; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Fanslau C; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Haarhoff Z; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Huang C; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Kramer M; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Menard K; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Monereau L; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Morrison J; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Ranasinghe A; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Shields EE; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Tye CK; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Westhouse R; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Everlof G; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Sheriff S; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Yan C; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Marsilio F; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Zhang L; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Zvyaga T; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Lee F; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Gavai AV; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
  • Degnan AP; Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.
Bioorg Med Chem Lett ; 44: 128108, 2021 07 15.
Article en En | MEDLINE | ID: mdl-33991625
ABSTRACT
We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Carbolinas / Proteínas / Desarrollo de Medicamentos / Mieloma Múltiple / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Carbolinas / Proteínas / Desarrollo de Medicamentos / Mieloma Múltiple / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article