Wang Yuting, Zhang Lenghe, Tang Xia, Luo Jinfeng, Tu Zhengchao, Jiang Kaili, Ren Xiaomei, Xu Fang, Chan Shingpan, Li Yuhua, Zhang Zhang, Ding Ke
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongYeDaDaoZhong, Guangzhou, Guangdong, 510280, China.
Transl Oncol. 2020 Apr;13(4):100766. doi: 10.1016/j.tranon.2020.100766. Epub 2020 Apr 1.
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 MV4-11, KG-1 and EOL-1 leukemia cells. It selectively inhibits the growth of MV4-11, KG-1 and EOL-1 cells, and also effectively suppresses the growth of Ba/F3-FLT3-ITD cells harboring F691I and other mutations with IC 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.
GZD824是一种新型的第三代BCR-ABL抑制剂。2019年，它在中国进入II期临床试验，在美国进入Ib期临床试验，用于治疗耐药慢性粒细胞白血病（CML）患者。我们发现，在浓度低于10 nM时，GZD824能显著抑制MV4-11、KG-1和EOL-1白血病细胞中的FLT3、FGFR1和PDGFRα激酶活性，并抑制其信号通路。它选择性地抑制MV4-11、KG-1和EOL-1细胞的生长，还能有效抑制携带F691I及其他突变、IC值<10 nM的Ba/F3-FLT3-ITD细胞的生长。GZD824诱导MV4-11、KG-1和EOL-1细胞发生G0/G1期阻滞和凋亡，并激活caspase-3和PARP的裂解。在MV4-11、Ba/F3-ITD-F691I和KG-1小鼠异种移植模型中，GZD824以10或20 mg/kg、q2d、口服给药，几乎能完全根除肿瘤。它还能抑制一名FLT3-ITD阳性AML患者的原发性白血病母细胞的活力，但对表达天然FLT3的细胞则无此作用。因此，GZD824可抑制FLT3-ITD驱动的AML白血病细胞以及由FGFR1或PDGFRα驱动的其他血液系统恶性肿瘤细胞，它可能被认为是一种治疗白血病的新型药物。
