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

Autor: Wang Shuxian, Yanle Zhi, Guo Xiaoxing, Cai Jiongheng, Zhang Liang, Shuai Lu, Yatian Huang, Hao Heng, Qin Tianren, Hongmei Li, Xiang Li, Wang Zhijie, Qing-Yuan Lan, Tao Lu, Yadong Chen
Rok vydání: 2019
Předmět:
Male
Cell
Antineoplastic Agents
Apoptosis
Pyrazole
Inhibitory postsynaptic potential
01 natural sciences
Rats
Sprague-Dawley
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Downregulation and upregulation
Cell Line
Tumor
hemic and lymphatic diseases
Drug Discovery
medicine
Animals
Humans
Protein Kinase Inhibitors
030304 developmental biology
Pharmacology
Mice
Inbred BALB C
0303 health sciences
Binding Sites
Molecular Structure
010405 organic chemistry
Organic Chemistry
Autophosphorylation
Myeloid leukemia
hemic and immune systems
General Medicine
Xenograft Model Antitumor Assays
0104 chemical sciences
Molecular Docking Simulation
Leukemia
Myeloid
Acute
medicine.anatomical_structure
fms-Like Tyrosine Kinase 3
chemistry
Mutation
embryonic structures
Toxicity
Microsomes
Liver
Cancer research
Pyrazoles
Female
Zdroj: European Journal of Medicinal Chemistry. 176:248-267
ISSN: 0223-5234
Popis: 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.
Databáze: OpenAIRE
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