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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.

SUBMITTER: Weisberg E

PROVIDER: S-EPMC2597611 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.

Weisberg Ellen E Roesel Johannes J Bold Guido G Furet Pascal P Jiang Jingrui J Cools Jan J Wright Renee D RD Nelson Erik E Barrett Rosemary R Ray Arghya A Moreno Daisy D Hall-Meyers Elizabeth E Stone Richard R Galinsky Ilene I Fox Edward E Gilliland Gary G Daley John F JF Lazo-Kallanian Suzan S Kung Andrew L AL Griffin James D JD

Blood 20080926 13

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 h ...[more]

PMID: 18820131

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Project description:Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation "type II" FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation "type II" derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between "type I" inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between "type I" and first-generation "type II" FLT3 inhibitors, the high potency of the second-generation "type II" inhibitors was sufficient to potently kill "type I" inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation "type II" inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of "type II" inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent "type I" inhibitors and "type II" first-generation FLT3 inhibitors cannot.

Dataset Information

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.

Publications

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.

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