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

التفاصيل البيبلوغرافية
العنوان: GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitroand In Vivo
المؤلفون: Wang, Yuting, Zhang, Lenghe, Tang, Xia, Luo, Jinfeng, Tu, Zhengchao, Jiang, Kaili, Ren, Xiaomei, Xu, Fang, Chan, Shingpan, Li, Yuhua, Zhang, Zhang, Ding, Ke
المصدر: Translational Oncology; April 2020, Vol. 13 Issue: 4
مستخلص: 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-FGFR1and EOL-1FIP1L1-PDGFRaleukemia cells. It selectively inhibits the growth of MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1and EOL-1FIP1L1-PDGFRacells, and also effectively suppresses the growth of Ba/F3-FLT3-ITD cells harboring F691I and other mutations with IC50values <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.
قاعدة البيانات: Supplemental Index
الوصف
تدمد:19447124
19365233
DOI:10.1016/j.tranon.2020.100766