Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mut
Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mut
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1-(4-(4-氨基-3-(4-(2-吗啉乙氧基)-苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯基)-3-(5的发现
DOI：
10.1021/acs.jmedchem.7b00840
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发表时间：
2017
影响因子：
7.3
通讯作者：
Liu Qingsong
中科院分区：
文献类型：
--
作者：
Wang Aoli;Li Xixiang;Chen Cheng;Wu Hong;Qi Ziping;Hu Chen;Yu Kailin;Wu Jiaxin;Liu Juan;Liu Xiaochuan;Hu Zhenquan;Wang Wei;Wang Wenliang;Wang Wenchao;Wang Li;Wang Beilei;Liu Qingwang;Li Lili;Ge Jian;Ren Tao;Zhang Shanchun;Xia Ruixiang;Liu Jing;Liu Qingsong
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, compound14(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 context14strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies14demonstrated an acceptable bioavailability (F= 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg–1day–1, TGI = 97%) without exhibiting obvious toxicity. Compound14might be a potential drug candidate for FLT3-ITD positive AML.
