jm9b00223_si_001.pdf (935.49 kB)
Download file

Identification of Pyrrolo[2,3‑d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia

Download (935.49 kB)
journal contribution
posted on 02.04.2019, 00:00 by Xue Yuan, Yong Chen, Wanhua Zhang, Jun He, Lei Lei, Minghai Tang, Jiang Liu, Muzhou Li, Caixia Dou, Tao Yang, Linyu Yang, Shengyong Yang, Yuquan Wei, Aihua Peng, Ting Niu, Mingli Xiang, Haoyu Ye, Lijuan Chen
A series of pyrrolo­[2,3-d]­pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities 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 the 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 the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate 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 acute myelogenous leukemia.

History