1区 · 医学
Article
作者: Wu, Hong ; Liu, Xiaochuan ; Zhang, Shanchun ; Li, Xixiang ; Wang, Wenchao ; Yu, Kailin ; Liu, Juan ; Liu, Jing ; Wang, Aoli ; Liu, Qingsong ; Liu, Qingwang ; Wu, Jiaxin ; Hu, Chen ; Wang, Wenliang ; Wang, Wei ; Ren, Tao ; Ge, Jian ; Xia, Ruixiang ; Qi, Ziping ; Li, Lili ; Wang, Beilei ; Wang, Li ; Chen, Cheng ; Hu, Zhenquan
FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg-1 day-1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.
