Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model

• Published in: European journal of medicinal chemistry 2019-08, Vol.176, p.248-267
• Main Authors: Heng, Hao, Wang, Zhijie, Li, Hongmei, Huang, Yatian, Lan, Qingyuan, Guo, Xiaoxing, Zhang, Liang, Zhi, Yanle, Cai, Jiongheng, Qin, Tianren, Xiang, Li, Wang, Shuxian, Chen, Yadong, Lu, Tao, Lu, Shuai
• Format: Article
• Language: English
• Subjects: AML; FLT3-ITD; Inhibitor; Selectivity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.021

FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML. [Display omitted] •46 was highly potent and specific against FLT3-ITD.•46 showed good antitumor efficacy in MV4-11 mouse xenograft model without decreasing the body weight of mice.