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Download file2‑Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors
journal contribution
posted on 31.03.2017, 00:00 by Cheng Mo, Zhang Zhang, Christopher P. Guise, Xueqiang Li, Jinfeng Luo, Zhengchao Tu, Yong Xu, Adam V. Patterson, Jeff B. Smaill, Xiaomei Ren, Xiaoyun Lu, Ke DingA 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.