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Download file2‑Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors
journal contribution
posted on 2017-03-31, 00:00 authored 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.