SEARCH:   Advanced

Blood, 15 December 2008, Vol. 112, No. 13, pp. 5161-5170. Prepublished online as a Blood First Edition Paper on September 26, 2008; DOI 10.1182/blood-2008-02-138065. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-02-138065v1 112/13/5161    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weisberg, E. Articles by Griffin, J. D. Search for Related Content PubMed PubMed Citation Articles by Weisberg, E. Articles by Griffin, J. D. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells Ellen Weisberg1,*, Johannes Roesel2,*, Guido Bold2, Pascal Furet2, Jingrui Jiang1, Jan Cools3, Renee D. Wright4, Erik Nelson1, Rosemary Barrett1, Arghya Ray1, Daisy Moreno5, Elizabeth Hall-Meyers5, Richard Stone1,6, Ilene Galinsky1, Edward Fox7, Gary Gilliland8, John F. Daley1, Suzan Lazo-Kallanian1, Andrew L. Kung4, and James D. Griffin1 1 Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA; 2 Novartis Pharma AG, Basel, Switzerland; 3 Department of Molecular and Developmental Genetics, Flanders Interuniversity, Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium; 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA; 5 Animal Resources Facility, Dana-Farber Cancer Institute, Boston, MA; 6 Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA; 7 Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, MA; and 8 Brigham and Women's Hospital, Boston, MA An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD+ leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. P. Zarrinkar, R. N. Gunawardane, M. D. Cramer, M. F. Gardner, D. Brigham, B. Belli, M. W. Karaman, K. W. Pratz, G. Pallares, Q. Chao, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood, October 1, 2009; 114(14): 2984 - 2992. [Abstract] [Full Text] [PDF] A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Blood, March 5, 2009; 113(10): 2302 - 2311. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020