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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