- 2-aminopyrimidine compounds and application thereof
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The invention relates to 2-aminopyrimidine compounds with structures as shown in a formula I which is described in the specification, and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof, belonging to the technical field of chemical medicines. The compounds are capable of realizing high-selectivity inhibition of the activity of the FGFR4 protein kinase without inhibition of the activities of other member kinases (i.e., FGFR1, FGFR2 and FGFR3) in the FGFRs family. The compounds can effectively inhibit the growth of tumor cells caused by the abnormity of a FGFR4 signaling pathway, and is applicable to prevention and treatment of transitional proliferative diseases such as tumors in human beings and other mammals caused by the abnormity of the FGFR4 signaling pathway.
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Paragraph 0119; 0123; 0125
(2018/09/28)
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- 2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors
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A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a Kd value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an IC50 value of 0.38 μM. Furthermore, 2n exhibited extraordinary target specificity in a Kinome-wide screen against 468 kinases, with S(35) and S(10) selectivity scores of 0.01 and 0.007 at 1.0 μM, respectively.
- Mo, Cheng,Zhang, Zhang,Guise, Christopher P.,Li, Xueqiang,Luo, Jinfeng,Tu, Zhengchao,Xu, Yong,Patterson, Adam V.,Smaill, Jeff B.,Ren, Xiaomei,Lu, Xiaoyun,Ding, Ke
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supporting information
p. 543 - 548
(2017/05/19)
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