Reference Detail

Ref Type

Journal Article

PMID

(12124172)

Authors

Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG, Giese NA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	1	5	2002 Jun	421-32	Cancer Cell

URL

Abstract Text

Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.

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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
Tandutinib	Tandutinib	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Tandutinib		MLN518\|CT53518\|CT-53518\|MLN-518	FLT3 Inhibitor 66 KIT Inhibitor 57 PDGFR-beta Inhibitor 14	Tandutinib (CT53518) is a tyrosine kinase inhibitor of FLT3, KIT, and PDGFRbeta, which inhibits cell proliferation and induces apoptosis (PMID: 12166950, PMID: 12124172, PMID: 27663390).

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 R595_L601dup	acute myeloid leukemia	sensitive	Tandutinib	Preclinical	Actionable	In a preclinical study, tandutinib (CT53518) inhibited cell proliferation in cell culture and in mouse models carrying FLT3 L601_K602insREYEYDL (PMID: 12124172).	12124172
FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE	acute myeloid leukemia	sensitive	Tandutinib	Preclinical	Actionable	In a preclinical study, tandutinib (CT53518) inhibited proliferation of cells expressing FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE in culture (PMID: 12124172).	12124172
FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL	acute myeloid leukemia	sensitive	Tandutinib	Preclinical - Cell culture	Actionable	In a preclinical study, tandutinib (CT53518) inhibited proliferation of cells expressing FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL in culture (PMID: 12124172).	12124172
FLT3 Y599_D600insGLYVDFREYEY	acute myeloid leukemia	sensitive	Tandutinib	Preclinical	Actionable	In a preclinical study, tandutinib (CT53518) inhibited proliferation of cells expressing FLT3 Y599_D600insGLYVDFREYEY in culture (PMID: 12124172).	12124172
FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG	acute myeloid leukemia	sensitive	Tandutinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tandutinib (CT53518) inhibited proliferation of cells expressing FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG in culture (PMID: 12124172).	12124172