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

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

  • Eur J Med Chem. 2019 Aug 15;176:248-267. doi: 10.1016/j.ejmech.2019.05.021.
Hao Heng 1,  Zhijie Wang 1,  Hongmei Li 1,  Yatian Huang 1,  Qingyuan Lan 1,  Xiaoxing Guo 1,  Liang Zhang 1,  Yanle Zhi 2,  Jiongheng Cai 3,  Tianren Qin 3,  Li Xiang 3,  Shuxian Wang 3,  Yadong Chen 4,  Tao Lu 5,  Shuai Lu 6
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
  • 3 School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 4 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: chenyadong@gmail.com.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 6 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: lu_shuai@cpu.edu.cn.
PMID: 31103903 DOI: 10.1016/j.ejmech.2019.05.021
Abstract

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.

Keywords

AML; FLT3-ITD; Inhibitor; Selectivity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128572
    99.14%, FLT3抑制剂
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