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A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia.
Woessner, D W; Eiring, A M; Bruno, B J; Zabriskie, M S; Reynolds, K R; Miller, G D; O'Hare, T; Deininger, M W; Lim, C S.
Afiliación
  • Woessner DW; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
  • Eiring AM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
  • Bruno BJ; Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
  • Zabriskie MS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
  • Reynolds KR; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
  • Miller GD; Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
  • O'Hare T; 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
  • Deininger MW; 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
  • Lim CS; 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
Leukemia ; 29(8): 1668-75, 2015 Aug.
Article en En | MEDLINE | ID: mdl-25721898
Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CC(mut3), which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CC(mut3) exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CC(mut3) inhibits colony formation by primary CML CD34(+) cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas de Fusión bcr-abl / Mutación Puntual / Resistencia a Antineoplásicos / Multimerización de Proteína Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas de Fusión bcr-abl / Mutación Puntual / Resistencia a Antineoplásicos / Multimerización de Proteína Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido