1453211-80-7Relevant articles and documents
Discovery and optimization of selective FGFR4 inhibitors via scaffold hopping
Wang, Yikai,Chen, Zhengxia,Dai, Meibi,Sun, Peipei,Wang, Chunqiu,Gao, Yang,Zhao, Haixia,Zeng, Wenqin,Shen, Liang,Mao, Weifeng,Wang, Tian,Hu, Guoping,Li, Jian,Chen, Shuhui,Long, Chaofeng,Chen, Xiaoxin,Liu, Junhua,Zhang, Yang
, p. 2420 - 2423 (2017)
Introduction of a Michael acceptor on a flexible scaffold derived from pan-FGFR inhibitors has successfully yielded a novel series of highly potent FGFR4 inhibitors with selectivity over FGFR1. Due to reduced lipophilicity and aromatic ring count, this series demonstrated improved solubility and permeability. However, plasma instability and fast metabolism limited its potential for in vivo studies. Efforts have been made to address these problems, which led to the discovery of compound (?)-11 with improved stability, CYP inhibition, and good activity/selectivity for further optimization.
2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors
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
supporting information, p. 543 - 548 (2017/05/19)
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.
