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Ref Type Journal Article
PMID (12815052)
Authors Murata K, Kumagai H, Kawashima T, Tamitsu K, Irie M, Nakajima H, Suzu S, Shibuya M, Kamihira S, Nosaka T, Asano S, Kitamura T
Title Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3).
Abstract Text The receptor tyrosine kinase FLT3 is constitutively activated by an internal tandem duplication (ITD) mutation within the juxtamembrane domain in 20-30% of patients with acute myeloid leukemia. In this study, we identified GTP-14564 as a specific kinase inhibitor for ITD-FLT3 and investigated the molecular basis of its specificity. GTP-14564 inhibited the growth of interleukin-3-independent Ba/F3 expressing ITD-FLT3 at 1 microM, whereas a 30-fold higher concentration of GTP-14564 was required to inhibit FLT3 ligand-dependent growth of Ba/F3 expressing wild type FLT3 (wt-FLT3). However, this inhibitor suppressed the kinase activities of wt-FLT3 and ITD-FLT3 equally, suggesting that the signaling pathways for proliferation differ between wt-FLT3 and ITD-FLT3. Analysis of downstream targets of FLT3 using GTP-14564 revealed STAT5 activation to be essential for growth signaling of ITD-FLT3. In contrast, wt-FLT3 appeared to mainly use the MAPK pathway rather than the STAT5 pathway to transmit a proliferative signal. Further analysis demonstrated that the first two tyrosines in an ITD were critical for STAT5 activation and growth induction but that all of the tyrosines in the juxtamembrane region were dispensable in terms of the proliferation signals of wt-FLT3. These results indicate that an ITD mutation in FLT3 elicits an aberrant STAT5 activation that results in increased sensitivity to GTP-14564. Thus, FLT3-targeted inhibition is an attractive approach, with the potential for selective cytotoxicity, to the treatment of ITD-FLT3-positive acute myeloid leukemia.


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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
GTP-14564 GTP-14564 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GTP-14564 GTP14564|GTP 14564 FLT3 Inhibitor 68 KIT Inhibitor 57 PDGFR-beta Inhibitor 14 GTP-14564 is a selective inhibitor of FLT3, c-Fms, c-Kit, and PDGFR-beta, which may result in reduced downstream signaling and subsequent reductions in cell proliferation and tumor growth (PMID: 12815052).
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 GTP-14564 Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring a FLT3 internal tandem duplication were sensitive to GTP-14564 treatment in culture, demonstrating growth inhibition (PMID: 12815052). 12815052
FLT3 exon 14 ins hematologic cancer sensitive GTP-14564 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing a FLT3 internal tandem duplication were sensitive to GTP-14564 treatment in culture, demonstrating decreased Stat5 activity and growth inhibition (PMID: 12815052). 12815052