酪氨酸激酶
受体酪氨酸激酶
布鲁顿酪氨酸激酶
激酶
突变体
SH2域
生物化学
蛋白质酪氨酸磷酸酶
T790米
对接(动物)
活动站点
蛋白激酶结构域
酶
帕纳替尼
酪氨酸
立体化学
作者
Deheng Sun,Yang Yu,Jiankun Lyu,Wei Zhou,Song Wenlin,Zhenjiang Zhao,Zhuo Chen,Yufang Xu,Honglin Li
标识
DOI:10.1021/acs.jmedchem.6b00374
摘要
FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G0/G1 cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for ...
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