Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Le

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• 作者：Xiaofei Liang ; Xiaochuan Liu ; Beilei Wang ; Fengming Zou ; Aoli Wang ; Shuang Qi ; Cheng Chen ; Zheng Zhao ; Wenchao Wang ; Ziping Qi ; Fengchao Lv ; Zhenquan Hu ; Li Wang ; Shanchun Zhang ; Qingsong Liu ; Jing Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1984-2004
• 全文大小：1158K
• ISSN：1520-4804

文摘

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.