SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase

Yee, Kevin; O’Farrell, Anne; Smolich, Beverly D.; Cherrington, Julie M.; McMahon, Gerald; Wait, Cecily L.; McGreevey, Laura; Griffith, Diana; Heinrich, Michael C.

doi:10.1182/blood-2002-02-0531

Cited by 158 publications

(138 citation statements)

References 50 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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“…39 The MV 4-11 AML cell line, originally established from a patient with a AML FAB 5, carries FLT3 ITD. 40 To test the specificity of action of perifosine, we evaluated by flow cytometry its effects on both p-Akt and p-FLT3 levels in MV 4-11 AML cells. As a negative control for both antigens, we employed HL60 cells ( Figure 5).…”

Section: Perifosine Downregulates P-akt But Not P-flt3 Levels In MV mentioning

confidence: 99%

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

et al. 2007

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The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34 þ cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.

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“…STAT5 appears to be an important target molecule in constitutively activated FLT3-mediated leukaemogenesis, and its phosphorylation is inhibited by selective FLT3 tyrosine kinase inhibitors (Levis et al, 2001(Levis et al, , 2002Tse et al, 2001;Weisberg et al, 2002;Yee et al, 2002). FLT3/ITD signalling also has been shown to activate phosphatidylinositol 3-kinase (PI3K)/Akt pathways (Hayakawa et al, 2000;Mizuki et al, 2000), leading to protection from apoptosis.…”

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confidence: 99%

Constitutively activated FLT3 phosphorylates BAD partially through Pim‐1

2006

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SummaryConstitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukaemogenesis and their presence is associated with a poor prognosis in acute myeloid leukaemia (AML). Examining the anti-and proapoptotic proteins in constitutively activated FLT3 signalling in BaF3/ITD and MV4-11 cells, we found that the level of Bcl-2 antagonist of cell death (BAD) phosphorylation was greatly decreased in response to FLT3 inhibition. Both Ser-112 and Ser-136 of BAD are rapidly dephosphorylated after treatment with the FLT3 inhibitor CEP-701 in BaF3/ITD and MV4-11 cells. In confirmation of the cell line data, BAD was highly phosphorylated in both constitutively activated wild-type and mutant FLT3 primary AML samples, and rapidly dephosphorylated after treatment of the primary samples with CEP-701. Upstream proteins known to phosphorylate BAD include Akt, extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/ MAPK), Pim-1 and Pim-2. We and other groups have shown that constitutively activated FLT3 induces multiple signalling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, Erk/MAPK and Janus kinase/signal transducers and activators of transcription (Jak/STAT). Thus, BAD may be a nexus point upon which these multiple signalling pathways converge in FLT3-mediated cell survival. In support of this, siRNA knockdown of BAD expression in MV4-11 cells conferred resistance to CEP-701-mediated apoptosis. Our data suggests that Pim-1 is one of the principal kinases mediating the anti-apoptotic function of FLT3/ITD signalling via the phosphorylation of BAD.

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SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase

Cited by 158 publications

References 50 publications

FLT3: ITDoes matter in leukemia

FLT3: ITDoes matter in leukemia

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

Constitutively activated FLT3 phosphorylates BAD partially through Pim‐1

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