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Ref Type

Journal Article

PMID

(15815726)

Authors

Komeno Y, Kurokawa M, Imai Y, Takeshita M, Matsumura T, Kubo K, Yoshino T, Nishiyama U, Kuwaki T, Osawa T, Ogawa S, Chiba S, Miwa A, Hirai H

Title

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	19	6	2005 Jun	930-5	Leukemia

URL

Abstract Text

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.

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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
Ki23819	Ki23819	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ki23819			FLT3 Inhibitor 69	Ki23819 inhibits both wild-type FLT3 and FLT3 containing activating internal tandem duplications, which may block downstream signaling and induce apoptosis in cancer cells (PMID: 15815726).

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	Ki23819	Preclinical - Cell culture	Actionable	In a preclinical study, acute myeloid leukemia cells harboring a FLT3 internal tandem duplication were sensitive to Ki23819 in culture, demonstrating inhibition of autophosphorylation and downstream signaling, and reduced cell proliferation (PMID: 15815726).	15815726