Journal of Medicinal Chemistry p. 1984 - 2004 (2016)
Update date:2022-08-15
Topics:
Liang, Xiaofei
Liu, Xiaochuan
Wang, Beilei
Zou, Fengming
Wang, Aoli
Qi, Shuang
Chen, Cheng
Zhao, Zheng
Wang, Wenchao
Qi, Ziping
Lv, Fengchao
Hu, Zhenquan
Wang, Li
Zhang, Shanchun
Liu, Qingsong
Liu, Jing
Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.
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