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A series of pyrrolo[2,3-d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutants cancer cells. Among them, compound 9u possessed of nanomolar FLT3 inhibitory activity and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in G0/G1 stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in MV4-11 xenograft model and significantly inhibited the tumor growth in MOLM-13 xenograft model with TGI of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability (F=59.5%) and suitable eliminated half-life time (T1/2=2.06 h), suggesting that 9u may be a potent candidate for treating AML.
This article was published in the following journal.
Name: Journal of medicinal chemistry
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