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Translational Oncology
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Translational Oncology
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Translational Oncology
Article . 2020
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GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo

Authors: Yuting Wang; Lenghe Zhang; Xia Tang; Jinfeng Luo; Zhengchao Tu; Kaili Jiang; Xiaomei Ren; +5 Authors

GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo

Abstract

GZD824 is a novel third-generation BCR-ABL inhibitor. It entered Phase II clinical trials in China and Phase Ib clinical trials in USA in 2019 for treatment of patients with resistant chronic myeloid leukemia (CML). We found that at concentrations below 10 nM, GZD824 significantly suppresses FLT3, FGFR1 and PDGFRα kinase activities and inhibits their signal pathways in MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa leukemia cells. It selectively inhibits the growth of MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa cells, and also effectively suppresses the growth of Ba/F3-FLT3-ITD cells harboring F691I and other mutations with IC50 values <10 nM. GZD824 induces G0/G1 phase arrest and apoptosis in MV4-11, KG-1 and EOL-1 cells and activates cleavage of caspase-3 and PARP. In MV4-11, Ba/F3-ITD-F691I and KG-1 mouse xenograft models, GZD824 at 10 or 20 mg/kg, q2d, p.o. almost completely eradicates tumors. It also inhibits the viability of primary leukemic blasts from a FLT3-ITD positive AML patient but not those expressing native FLT3. Thus GZD824 suppresses leukemia cells of FLT3-ITD-driven AML and other hematologic malignancies driven by FGFR1 or PDGFRa, and it may be considered to be a novel agent for the treatment of leukemia.

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Keywords

Original article, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
19
Top 10%
Top 10%
Top 10%
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