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Anti-Leukemic Effects of Novel First and Second generation FLT3 Inhibitors: Structure-Affinity Comparison

Weisberg, Ellen, Roesel, Johannes, Furet, Pascal, Bold, Guido, Imbach, Patricia, Floersheimer, Andreas, Jiang, Jingrui, Manley, Paul W., Ray, Arghya and Griffin, James D (2010) Anti-Leukemic Effects of Novel First and Second generation FLT3 Inhibitors: Structure-Affinity Comparison. Genes & Cancer, 1 (10). pp. 1021-1032. ISSN 1947-6019


Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients that 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. Thus, we present two structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the anti-leukemic effects “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.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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