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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 Cancer cell
Vol 1
Issue 5
Date 2002 Jun
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 55 KIT Inhibitor 51 PDGFR-beta Inhibitor 13 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 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 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 F612_G613insGYVDFREYEYDLKWEFRPRENLEF acute myeloid leukemia sensitive Tandutinib Preclinical - Cell culture Actionable In a preclinical study, Tandutinib (CT53518) inhibited proliferation of cells expressing FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLEF in culture (PMID: 12124172). 12124172
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