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2‑Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors

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journal contribution
posted on 31.03.2017, 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 Ding
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.

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