title: Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.
abstract: 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.
authors.affiliation: Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Johannes
authors.initials: J
authors.lastname: Roesel
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Jingrui
authors.initials: J
authors.lastname: Jiang
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: Erik
authors.initials: E
authors.lastname: Nelson
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barrett
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Daisy
authors.initials: D
authors.lastname: Moreno
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hall-Meyers
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Edward
authors.initials: E
authors.lastname: Fox
authors.forename: Gary
authors.initials: G
authors.lastname: Gilliland
authors.forename: John F
authors.initials: JF
authors.lastname: Daley
authors.forename: Suzan
authors.initials: S
authors.lastname: Lazo-Kallanian
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002224:Carbanilides / Q000494:pharmacology*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D051379:Mice; D050505:Mutant Proteins / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D002224:Carbanilides; D050505:Mutant Proteins; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; D051941:fms-Like Tyrosine Kinase 3; C522130:NVP-AST487; D010671:Phenylurea Compounds; D011743:Pyrimidines; C497970:FLT3 protein, human; C059539:midostaurin