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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 Blood
Vol 123
Issue 14
Date 2014 Apr 3
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
G-749 G-749 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
G-749 FLT3 Inhibitor 55 G-749 is an inhibitor of both wild-type and mutant forms of FLT3, which may reduce cancer cell proliferation and tumor growth (PMID: 24532805, PMID: 30514344).
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 N676D FLT3 D835Y hematologic cancer sensitive G-749 Preclinical - Cell culture Actionable In a preclinical study, cells co-expressing FLT3 D835Y and FLT3 N676D were sensitive to G-749 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805). 24532805
FLT3 exon 14 ins acute myeloid leukemia sensitive G-749 Preclinical - Cell line xenograft Actionable In a preclinical study, G-749 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 exon 14 ins acute myeloid leukemia sensitive Cytarabine + G-749 Preclinical - Cell culture Actionable In a preclinical study, the combination of G-749 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 D835Y hematologic cancer sensitive G-749 Preclinical - Cell culture Actionable In a preclinical study, cells expressing FLT3 D835Y were sensitive to G-749 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805). 24532805
FLT3 exon 14 ins FLT3 N676D hematologic cancer sensitive G-749 Preclinical - Cell culture Actionable In a preclinical study, cells co-expressing a FLT3 internal tandem duplication and FLT3 N676D were sensitive to G-749 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805). 24532805
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive G-749 Preclinical - Cell culture Actionable In a preclinical study, cells co-expressing a FLT3 internal tandem duplication and FLT3 F691L were sensitive to G-749 in culture, demonstrating inhibition of cell growth and inhibition of Flt3 autophosphorylation (PMID: 24532805). 24532805