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Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax).
Leverson, J D; Zhang, H; Chen, J; Tahir, S K; Phillips, D C; Xue, J; Nimmer, P; Jin, S; Smith, M; Xiao, Y; Kovar, P; Tanaka, A; Bruncko, M; Sheppard, G S; Wang, L; Gierke, S; Kategaya, L; Anderson, D J; Wong, C; Eastham-Anderson, J; Ludlam, M J C; Sampath, D; Fairbrother, W J; Wertz, I; Rosenberg, S H; Tse, C; Elmore, S W; Souers, A J.
Afiliación
  • Leverson JD; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Zhang H; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Chen J; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Tahir SK; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Phillips DC; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Xue J; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Nimmer P; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Jin S; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Smith M; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Xiao Y; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Kovar P; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Tanaka A; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Bruncko M; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Sheppard GS; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Wang L; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Gierke S; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Kategaya L; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Anderson DJ; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Wong C; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Eastham-Anderson J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Ludlam MJ; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Sampath D; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Fairbrother WJ; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Wertz I; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Rosenberg SH; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Tse C; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Elmore SW; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Souers AJ; Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
Cell Death Dis ; 6: e1590, 2015 Jan 15.
Article en En | MEDLINE | ID: mdl-25590800
The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Apoptosis / Bibliotecas de Moléculas Pequeñas / Proteína 1 de la Secuencia de Leucemia de Células Mieloides / Compuestos de Anilina / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Apoptosis / Bibliotecas de Moléculas Pequeñas / Proteína 1 de la Secuencia de Leucemia de Células Mieloides / Compuestos de Anilina / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido