Reference Detail

Ref Type

Journal Article

PMID

(12351406)

Authors

Yee KW, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL, McGreevey LS, Griffith DJ, Heinrich MC

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	100	8	2002 Oct 15	2941-9	Blood

URL

Abstract Text

Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the type III RTK family. Given the conserved homology between members of this family, we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC(50)], 100 nM; and SU5614 IC(50) 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC(50), 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines. Treatment of these cells with an alternative growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Semaxanib	Semaxanib	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Semaxanib		SU5416\|Semoxind\|Sugen 5416	FLT3 Inhibitor 69 VEGFR1 Inhibitor 6 VEGFR2 Inhibitor 37	Semaxanib (SU5416) is an inhibitor of FLT1 (VEGFR1), KDR (VEGFR2), and FLT3, which inhibits tumor vascularization and growth (PMID: 9892193, PMID: 12351406, PMID: 29208523).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Semaxanib	Preclinical - Cell culture	Actionable	In a preclinical study, acute myeloid leukemia cells harboring a FLT3 internal tandem duplication were sensitive to Semaxanib (SU5416) in culture, demonstrating inhibition of cell proliferation and inhibition of Flt3, Mapk, and Stat5 phosphorylation (PMID: 12351406).	12351406