CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

Kelly, Louise; Yu, Jin‐Chen; Boulton, Christina; Apatira, Mutiah; Li, Jason; Sullivan, Carol M.; Williams, Ifor R.; Amaral, Sonia M; Curley, David P.; Duclos, Nicole; Neuberg, Donna; Scarborough, Robert M.; Pandey, Anjali; Hollenbach, Stanley J.; Abe, Keith; Lokker, Nathalie A.; Gilliland, D. Gary; Giese, Neill A.

doi:10.1016/s1535-6108(02)00070-3

Cited by 291 publications

(218 citation statements)

References 44 publications

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“…79 A number of additional small-molecule tyrosine kinase inhibitors with activity against FLT3 have now been identified (Table 5). 79,108,112,138,139,[141][142][143][144][145][146] These FLT3 inhibitors encompass a variety of chemical classes, but all are heterocyclic compounds containing a structural mimic of the purine component of ATP. While direct structural analysis of FLT3 is not yet available, analysis of the crystal structure data for a variety of other kinases bound to different small-molecule inhibitors allows some deductions to be made regarding the structure activity relationships of FLT3 inhibitors.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

FLT3: ITDoes matter in leukemia

2003

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FMS-like tyrosine kinase-3 (FLT3), a receptor tyrosine kinase, is important for the development of the hematopoietic and immune systems. Activating mutations of FLT3 are now recognized as the most common molecular abnormality in acute myeloid leukemia, and FLT3 mutations may play a role in other hematologic malignancies as well. The poor prognosis of patients harboring these mutations renders FLT3 an obvious target of therapy. This review summarizes the data on the molecular biology and clinical impact of FLT3 mutations, as well as the therapeutic potential of several small-molecule FLT3 inhibitors currently in development.

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Section: Flt3 Inhibitorsmentioning

confidence: 99%

FLT3: ITDoes matter in leukemia

2003

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“…A phase 2 study in relapsed/refractory patients with FLT3-ITD AML is currently recruiting patients, with interim data supporting doses of quizartinib 135 and 90 mg in men and women, respectively, due to QTc prolongation at a starting dose of 200 mg. 74 Tandutinib (MLN518) Tandutinib is more selective for FLT3 than midostaurin or lestaurtinib, although it does have some activity against plateletderived growth factor receptor-b and c-KIT. 75 Although tandutinib demonstrated some antileukemic activity as a single agent and in combination with chemotherapy in phase 1 studies, 76,77 doselimiting muscle weakness (reversible) and high rates of nausea and vomiting were observed. This may be related to the slow clearance and resultant high plasma levels of the drug.…”

Section: Quizartinib (Ac220)mentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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“…In a Phase I trial, KW-2449 treatment led to transient decreases in peripheral blast counts (Cortes et al, 2008;Pratz and Levis, 2008;Pratz et al, 2009 (Fiedler et al, 2005;Kancha et al, 2007;O'Farrell et al, 2003a, b), as well as the piperazinyl quinazoline MLN518 (tandutinib; CT53518; Millennium, Cambridge, MA, USA) (Kelly et al, 2002b;Cheng and Paz, 2008). There is presently an ongoing Phase I/II trial investigating SU11248 combined with standard chemotherapy in mutant FLT3-positive AML patients over the age of 60 years.…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

Cited by 291 publications

References 44 publications

FLT3: ITDoes matter in leukemia

FLT3: ITDoes matter in leukemia

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Drug resistance in mutant FLT3-positive AML

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