髓系白血病
效力
选择性
酪氨酸激酶
化学
激酶
Fms样酪氨酸激酶3
白血病
结构-活动关系
串联
药理学
癌症研究
突变
立体化学
体外
生物化学
生物
基因
受体
遗传学
材料科学
催化作用
复合材料
作者
Qing-Xin Wang,Yuhao Cao,Li-Jin Yang,Yi-Yuan Ma,Nan Li,Shi-Han Wu,Lu Chen,Jia-Zhen Wu,Zhen-Jiang Tong,Xiaolong Wang,Xin Xue,Ning Ding,Xuejiao Leng,Liang Chang,Wei-Chen Dai,Yan-Cheng Yu,Shan-Liang Sun,Ye Yang,Nian‐Guang Li,Zhi‐Hao Shi
出处
期刊:Future Medicinal Chemistry
[Newlands Press Ltd]
日期:2023-01-01
卷期号:15 (1): 57-71
标识
DOI:10.4155/fmc-2022-0231
摘要
Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.
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