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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.
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Submitted February 6, 2008
Accepted July 21, 2008
Anti-leukemic effects of the novel, mutant FLT3 inhibitor, NVP-AST487: Effects on PKC412-sensitive and -resistant FLT3-expressing cells
Ellen Weisberg, Johannes Roesel, Guido Bold, Pascal Furet, Jingrui Jiang, Jan Cools, Renee D. Wright, Erik Nelson, Rosemary Barrett, Arghya Ray, Daisy Moreno, Elizabeth Hall-Meyers, Richard Stone, Ilene Galinsky, Edward Fox, Gary Gilliland, John F. Daley, Suzan Lazo-Kallanian, Andrew L Kung, and James D. Griffin*
Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA, United States
Novartis Pharma AG, Basel, Switzerland
Department of Molecular and Developmental Genetics, Flanders University for Biotechnology (VIB), University of Leuven, Leuven, Belgium
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, United States
Animal Resources Facility, Dana Farber Cancer Institute, Boston, MA, United States
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States
Molecular Diagnostics Laboratory, Dana Farber Cancer Institute, Boston, MA, United States
Brigham and Women's Hospital, Boston, MA, United States
* Corresponding author; email: james_griffin{at}dfci.harvard.edu.
An attractive target for therapeutic intervention is constitutively-activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. 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 AML patients 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 anti-leukemic activity in an in vivo model of FLT3-ITD-positive leukemia. Finally, the combination of 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.
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