Reference Detail

Ref Type

Journal Article

PMID

(24532805)

Authors

Lee HK, Kim HW, Lee IY, Lee J, Jung DS, Lee SY, Park SH, Hwang H, Choi JS, Kim JH, Kim SW, Kim JK, Cools J, Koh JS, Song HJ

Title

G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	123	14	2014 Apr 3	2209-19	Blood

URL

Abstract Text

Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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	Cytarabine + SKI-G-801	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of SKI-G-801 and Cytosar-U (cytarabine) resulted in a synergistic effect, demonstrating greater inhibition of proliferation compared to G-749 alone in acute myeloid leukemia cells harboring a FLT3 internal tandem duplication (PMID: 24532805).	24532805
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	SKI-G-801	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SKI-G-801 induced apoptosis in acute myeloid leukemia cells harboring a FLT3 internal tandem duplication in culture, and inhibited tumor growth and induced tumor regression in cell line xenograft models (PMID: 24532805).	24532805
FLT3 N676D FLT3 D835Y	hematologic cancer	sensitive	SKI-G-801	Preclinical - Cell culture	Actionable	In a preclinical study, cells co-expressing FLT3 D835Y and FLT3 N676D were sensitive to SKI-G-801 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805).	24532805
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	sensitive	SKI-G-801	Preclinical - Cell culture	Actionable	In a preclinical study, cells co-expressing a FLT3 internal tandem duplication and FLT3 F691L were sensitive to SKI-G-801 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805).	24532805
FLT3 exon 14 ins FLT3 N676D	hematologic cancer	sensitive	SKI-G-801	Preclinical - Cell culture	Actionable	In a preclinical study, cells co-expressing a FLT3 internal tandem duplication and FLT3 N676D were sensitive to SKI-G-801 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805).	24532805
FLT3 D835Y	hematologic cancer	sensitive	SKI-G-801	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing FLT3 D835Y were sensitive to SKI-G-801 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805).	24532805